POZ Community Forums
Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: bimazek on September 20, 2007, 07:06:38 pm
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Two great new stories...
investigational integrase inhibitor elvitegravir
Elvitegravir is a dihydroquinoline carboxylic acid strand inhibitor of HIV integrase
Elvitegravir is a dihydroquinoline carboxylic acid
what it does is a strand inhibitor of HIV integrase
I am very excited about all these new -- call them -- second generation meds, that have lower toxicities and less side effects, they give me great hope, but i was curious as to what this substance was, where it came from what was it related to, obviously it is from natural substances here in the ground, i had a chem. professor in the family so i wanted to learn more and the findings are very re-assuring, to me at least, because the nukes and non nukes, seem scary in thier history and side effects, these new ones seem more specialized and rare yet somehow familiar and historic. after reading about this one it seems less mysterous and more acceptable
dihydroquinoline carboxylic acid
Quinoline - Wikipedia, the free encyclopediaQuinoline, also known as 1-azanaphthalene, 1-benzazine, or benzopyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a ...
en.wikipedia.org/wiki/Quinoline
http://www.chemicalland21.com/specialtychem/finechem/QUINALDINE.htm Quinaldine, 2-methylquinoline, is used as an anti-malaria and preparing other anti-malaria drugs. It is used in manufacturing oil soluble dyes, food colorants, pharmaceuticals, pH indicators and other organic compounds. Quinaldic Acid is a carboxylic acid substituted quinoline at 2 position, a catabolite of tryptophan (aromatic side chain amino acid). Quinazoline, diazanaphthalene at 1,3 positions, is used as a chemical intermediate for making medicines and other organic compounds. It is a fundamental structure in some antihypertensive agents such as prazosin and doxazosin which are peripheral vasodilator. Quinoxaline, diazanaphthalene at 1,4 positions, is used as a chemical intermediate for making fungicides and other organic compounds
http://chemicalland21.com/industrialchem/organic/QUINOLINE.htm#
carboxylic acid
http://en.wikipedia.org/wiki/Carboxylic_acid
http://www.chemicalland21.com/specialtychem/finechem/QUINALDINE.htm
Quinoline itself is the simplest member of the quinoline. It is a hygroscopic, liquid; slightly soluble in water, soluble alcohol, ether, carbon disulfide and readily in many organic solvents. It can be obtained by the distillation of coal tar. Quinoline family compounds are widely used as a parent compound to make drugs (especially anti-malarial medicines), fungicides, biocides, alkaloids, dyes, rubber chemicals and flavoring agents. They have antiseptic, antipyretic, and antiperiodic properties. They are also used as catalyst, corrosion inhibitor, preservative, and as solvent for resins and terpenes.
originally discovered in the distillation of coal tar.
monoclonal antibody PRO 140
this is a major major breakthru
The antibody PRO 140 produced a quick and prolonged reduction in viral load starting within five days. Some patients on the drug had a reduction by a factor of 10. After 10 days the average reduction was close to a factor of 1,000. Additionally, "the decline persisted for two to three weeks", Dr. Jacobson said.
http://www.associatedcontent.com/article/386600/new_monoclonal_antibody_blocks_hiv.html
this answers the question of a few months ago that we were posting about very simply and not too dramatically
60% greater risk of developing a non-AIDS-defining cancer for HIV-positive
http://www.aidsmap.com/en/news/55D50883-6979-4993-AC0A-53CFFA8F86F8.asp
A total of 33,420 HIV-infected patients were followed for a median of 5.1 years, with 66,840 HIV-negative individuals followed for a median of 6.4 years. Incidence rates of non-AIDS-defining cancers were 1260 per 100,000 person years in HIV-positive patients and 841 per 100,000 person years in HIV-negative patients. This corresponds to a 60% greater risk of developing a non-AIDS-defining cancer for HIV-positive versus HIV-negative patients (incidence rate ratio [IRR], 1.6; 95% CI: 1.5 – 1.7). The incidence of anal cancer (IRR 14.9; 95% CI: 10.1 – 22.1), Hodgkin’s lymphoma (IRR: 4.6; 95% CI: 3.6 – 6.6), liver cancer (IRR: 2.8; 95% CI: 2.2 – 3.5), and lung cancer (IRR 2.0; 95% CI: 1.7 – 2.2) were particularly elevated in HIV-positive individuals compared to HIV-uninfected patients.
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2006 article about new peptide assays for epitope discovery and vaccine research tool made by Sigma-Genosys (www.sigma-genosys.com
this article describes why vaccine research has been moving ahead recently because new tools to try lots of different epitopes or fragments can be produced using this companies tools
A major challenge in the development of vaccines is the difficulty of finding the right immunogenic element that can achieve an efficient and long-lasting immunization effect. Considerable effort has been made to find suitable fragments (protein epitopes) that can be included in vaccines to offer protection against serious life-threatening diseases.
http://www.genengnews.com/articles/chitem.aspx?aid=1882
peptide synthesis was historically an expensive choice in vaccine research and epitope mapping. However, a new synthesis platform from Sigma-Genosys (www.sigma-genosys.com) allows the rapid parallel synthesis of custom libraries at reduced costs, giving access to high-throughput synthetic peptide assays for epitope discovery and vaccine research. Epitope Mapping with Peptide Libraries
HIV exemplifies the time-consuming and difficult nature of vaccine discovery.
As CD8+ T cells have been shown to play an important role in containing HIV infection, vaccine development has focused on the biological mechanism of CD8+ T-cell responses upon HIV infection.
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Investigators Engineer T Cells against B-Cell ... this technique now proven in this study will be tried against any number of diseases now and in future, it is a nice new growth in science and could have some great and interesting results for hiv, seems to be a whole new branch of treatment, not vaccine, not medicine, in a way it is genetic engineered but not really old style gene therapy, call it immune system T cell engineering or immune system T cell gene modification
http://www.genengnews.com/news/bnitem.aspx?name=23253604&source=genwire
Investigators Engineer T Cells against B-Cell Malignancies
Sep 18 2007, 12:34 PM EST
GEN News Highlights
Modified T cells can be effective in fighting cancers associated with B cells such as acute lymphoblastic leukemia (ALL), according to researchers at Memorial Sloan-Kettering Cancer Center (MSKCC). By administering repeated doses of T cells designed to express an artificial receptor that recognizes human B cells, the researchers say that they were able to eradicate cancer in 44% of mice bearing human ALL tumors.
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gag region -- vaccine researchers should focusing on it
13 Sep 2007
a vaccine containing the correct part of the gag gene could activate the body's immune response and increase its ability to stop HIV-2 from progressing to AIDS. According to Aleksandra Leligdowicz, who leads the MRC unit, the latest research suggests that it is possible to create a vaccine that will not prevent infection or eradicate the virus but that could prevent progression to AIDS. "Clearly there is something special about the gag region -- and it looks like vaccine researchers should be focusing on it," Leligdowicz said. Most strains of HIV-1 also have a gag gene, according to Leligdowicz, who added that the 2% of people who test positive for HIV-1 and do not progress to AIDS also demonstrate a strong immune response to the gene
http://www.medicalnewstoday.com/articles/82159.php
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http://afp.google.com/article/ALeqM5ju0Xe3NMXSNs_si-VJRa47qKY51Q
"These findings may serve as the basis for a new strategy to develop a new class of anti-HIV drugs, the splicing inhibitors, and even of antiviral drugs in general, since any virus needing to splice its RNAs may be targeted," his team writes.
However, exhaustive tests on lab animals, leading to cautious trials on humans, are needed before IDC16 can be certified as safe and effective. This process typically takes years.
good new dev. on the p-mRNA area will be year out in future ... but every good step helps
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Wow -- this is fantastic -- this is a new trial with very exciting words... the trial with this med MDX-1106 for melanoma cancer must have worked well enough for them to want to try a viral cancer disease like hepatitis and the fact that it is in trials is life saving!!! I wont even mention that this is anti-pd-1 fully human monoclonal antibody. If you have cancer from hep C try to get in this trial.
http://www.medarex.com/cgi-local/item.pl/20071029-1069064
Oct. 29 2007
Medarex, Inc. (Nasdaq: MEDX) announced today the allowance of an investigational
new drug application (IND) filed with the U.S. Food & Drug Administration (FDA)
for MDX-1106 (ONO-4538: development code of Ono Pharmaceutical Co., Ltd.), a fully
human anti-PD-1 antibody being investigated for the treatment of chronic viral
infections, with the first trial to target hepatitis C. MDX-1106 was developed under
the May 2005 collaborative research agreement between Ono and Medarex, and currently
is in a separate ongoing Phase I clinical study in patients with recurrent or
treatment- refractory cancer. "Recently, involvement of PD-1 in hepatitis C has been reported in the
scientific literature," said Shozo Matsuoka, Ph.D., Senior Managing Director of Ono
Pharmaceutical, Co., Ltd. "ONO-4538/MDX-1106 aims to improve the immune capacity of
the body and treat hepatitis C with a novel mechanism of action which inhibits the
involvement of PD-1. We are seeking to develop ONO- 4538/MDX-1106 to be a new
treatment for hepatitis C."
http://www.rttnews.com/sp/Quickfactsnew.asp?date=10/29/2007&item=228
FDA Allows Ono And Medarex' Investigational New Drug Application For Fully Human Anti-PD1 Antibody [MEDX]
10/29/2007 5:03:39 PM Ono Pharmaceutical Co., Ltd. (OPHLF.PK) and Medarex, Inc. (MEDX) announced the allowance of an investigational new drug application filed with the U.S. Food & Drug Administration for MDX-1106, a fully human anti-PD-1 antibody being investigated for the treatment of chronic viral infections, with the first trial to target hepatitis C.
"treatment of chronic viral infections, with the first trial to target hepatitis C. "
this phrase is so so beautiful to me... because it is a very strong statement for a public drug company, it is a strong hint that in the future other chronic viral infections may be in trials and treated with this drug...
um lets see -- what chronic viral infection do we know is hugely impacted by this type of treatment
HIV
this could be an amazing hopeful thing, and they are moving to new clinical trials,
the first one was melanoma of the skin, rather easy to see the good effects, if the protein the monoclonal antibody protein works then the skin lesion gets smaller, very easy to see good results, this trial was so successful, they went back to FDA and with the results got approval to try with
chronic viral infections
first of which will be HepC cancer
BTW the word for cancer and tired are the same in latin and the latin language portugese.
i guess in anchient days being tired all the time was thought of as a cancer.
this is very very exciting to me and i must say that this could mean some great things
this means that the dose they were giving to melanoma patients was fine and did not have any bad adverse effects of the horrible kind, so the FDA is letting them try it on more deep and hidden disease.
kudos to who?
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Articles on HIV found by Google Scholar
In 2007 in Science articles that talk about HIV
26,300 articles in google scholar when we Search only in Medicine, Pharmacology, and Veterinary Science.
476 articles in Computer Science, and Mathematics. about HIV
2,290 articles in Chemistry and Materials Science.
82 articles for hiv. Search only in Physics,
Search only in Engineering, Computer Science, and Mathematics. 476 for hiv
http://scholar.google.com/scholar?hl=en&lr=&q=hiv&as_ylo=2007&as_yhi=2007&btnG=Search&as_allsubj=some&as_subj=eng
2,290 for hiv
Search only in Chemistry and Materials Science.
http://scholar.google.com/scholar?hl=en&lr=&q=hiv&as_ylo=2007&as_yhi=2007&btnG=Search&as_allsubj=some&as_subj=chm
26,300 for hiv
Search only in Medicine, Pharmacology, and Veterinary Science.
http://scholar.google.com/scholar?as_q=hiv&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=&as_publication=&as_ylo=2007&as_yhi=2007&as_allsubj=some&as_subj=med&hl=en&lr=
82 for hiv. Search only in Physics, Astronomy, and Planetary Science.
http://scholar.google.com/scholar?q=hiv&hl=en&lr=&as_ylo=2007&as_yhi=2007&as_subj=phy&start=10&sa=N
8,670 for hiv Search only in Social Sciences, Arts, and Humanities.
http://scholar.google.com/scholar?as_q=hiv&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=&as_publication=&as_ylo=2007&as_yhi=2007&as_allsubj=some&as_subj=soc&hl=en&lr=
Search only in Business, Administration, Finance, and Economics.
717 for hiv
http://scholar.google.com/scholar?as_q=hiv&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=&as_publication=&as_ylo=2007&as_yhi=2007&as_allsubj=some&as_subj=bus&hl=en&lr=
Each of these articles had a team of writers and researchers.
Also staff and secretaries, deans, and admin, and wives and husbands.
In can only be said that a vast effort by much of mankind is trying to solve this terrible disease, and every day they get closer
Just based on the recent successes in the vaccine trials, (not that one failure) and also gene, and many many new drug modalities
I must say that I agree, if someone is exposed today they should count on a normal lifespan and normal functionality.
For those infected ten and twenty years ago there are so many new new things coming out please work hard to stay in the game we all need you. And dont forget to give your time to those newly infected we all need you too.
71,700 for hiv total articles in all areas
hope this find interesting stuff for you
many interesting areas of research
into HIV
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ok here is the scoop, science discovered in last few years that 9% of the entire human genome is RETROVIRUSES that got stuck in the dna in the last 700 million years of evolution
literally every human has tons of virus code dna in thier bodies at birth from the time we were lower animals
sounds amazing but true
now they also discovered that sometimes one of these dna fragments called
endogenous retroviruses (HERV)
break free of the cell and start to multiply and in some cases cause some horrible very rare diseases, so rare that only like 23 people in usa get them a year and science didnt know what caused them till recently
anyway
NOW they have found a way
well first i should say that the body immune system since it has evolved with these DEEP dna retroviruses inside the human is very very good at keeping them suppressed in like 99.999% of humans
the dna is there but the molecules of immune system keep them shut up
so the new thing they found is that
they can use the part of the immune system that
DOES SUCH A GREAT JOB OF SUPPRESSING THE
DEEP
endogenous retroviruses (HERV)
THAT THEY CAN harness this part of immune system to fight HIV
and it works well
so they can make a vaccine with this info
it is a few years off but could pay off big in HIV and other rare rare terrible diseases.
http://www.google.com/search?hl=en&q=Novel+HIV+Vaccine+Target+Discovered&btnG=Google+Search
Novel HIV Vaccine Target Discovered
Nov 9 2007,
GEN News Highlights
Researchers identified a potential new way of fighting HIV infection that relies on the remnants of ancient viruses, human endogenous retroviruses (HERV). Mounting evidence suggests that HIV infection could enable HERV expression by disrupting the normal controls that keep HERV in check. In some HIV-infected individuals this induces infection fighting T cells to target HERV expressing cells.
"HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide,”
“These characteristics suggest that elicitation of antiHERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant,”
http://en.wikipedia.org/wiki/Endogenous_retrovirus
It is believed that the ancestors of modern vivipary mammals evolved after an accidental infection to an ancestor to this virus, that permitted to the fetus to survive the immune system of the mother. [1]
During pregnancy in viviparous mammals (all mammals except Monotremes), ERVs are activated and produced in high quantities during the implantation of the embryo. They are currently known to act as immunodepressors, protecting the embryo from its mothers immune system. Also viral fusion proteins apparently cause the formation of the placental syncytium in order to limit the exchange of migratory cells between the developing embryo and the body of the mother (something an epithelium will not do sufficiently, as certain blood cells are specialized to be able to insert themselves between adjacent epithelial cells)
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http://freshnews.com/news/biotech-biomedical/article_40893.html
DNA Vaccine Overview at Scientific Meeting
DNA vaccines have the potential to by-pass inherent scientific obstacles of conventional vaccines that prevent their development for cancer and chronic infectious diseases such as HIV and hepatitis C. Pre-clinical data has indicated the ability of Inovio’s technologies to effectively deliver and significantly enhance the potency of such immunotherapies without the potential safety concerns of viral delivery systems.
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http://www.freshnews.com/news/biotech-biomedical/article_40886.html?
Invitrogen and CytRx Subsidiary Rxi Pharmaceuticals Collaborate to Enhance RNAi
http://www.cytrx.com/vaccine_overview.html
http://www.cytrx.com/hiv_program.html
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http://freshnews.com/news/biotech-biomedical/article_40943.html
Dr. Taylor documented that 60% of circulating exosomes were removed from the blood of ovarian cancer patients during first pass (approximately 10-minutes) through a small scale Hemopurifier®. The capture data was consistent over the course of five different studies.
Hemopurifier® efficiently captures tumor secreted exosomes that inhibit the ability of the immune system to combat cancer. In follow-on studies, led by Dr. Douglas Taylor at the University of Louisville, it has now been demonstrated that the capture of exosomes by the Hemopurifier® does result in reversing immunosuppressive activity. Dr. Taylor is a recognized authority on the causative effects of immune suppression in cancer patients. He is credited with the initial characterization of exosomes and is a leading peer reviewed author on the subject.
“Based on emerging data, we envision the Hemopurifier® will become a treatment standard that enhances the benefit of therapies administered to those who suffer from cancer,” stated James A. Joyce, Chairman and CEO of Aethlon Medical.
http://www.imquest.com/hiv-agent.shtml
http://freshnews.com/news/biotech-biomedical/article_40882.html
http://www.aethlonmedical.com/technology/hemopurifier.htm
http://www.aethlonmedical.com/technology/reports.htm
Aethlon Medical is the developer of the Hemopurifier®, a first-in-class medical device to treat infectious disease. The Hemopurifier® addresses the largest opportunity in infectious disease, the treatment of drug and vaccine resistant viruses. Regulatory and commercialization initiatives in the United States are focused on bioterror threats, while international initiatives are directed towards naturally evolving pandemic threats, and chronic infectious disease conditions including Hepatitis-C (HCV) and the Human Immunodeficiency Virus (HIV). Collaborative studies to demonstrate utility of the Hemopurifier® are being conducted with researchers at the Government of India’s National Institute of Virology (NIV), The Centers for Disease Control and Prevention (CDC), The United States Army Medical Research Institute of Infectious Diseases (USAMRIID), and The Southwest Foundation for Biomedical Research (SFBR). Aethlon recently demonstrated safety of the Hemopurifier® in a 24-treatment human study and is now conducting follow-on human studies at the Fortis Hospital in Delhi, India. The Company has also submitted an Investigational Device Exemption (IDE) to the U.S. Food and Drug Administration (FDA) related to advancing the Hemopurifier® as a broad-spectrum treatment countermeasure against category “A” bioterror threats. Additional information regarding Aethlon Medical and its Hemopurifier® technology can be accessed online at www.aethlonmedical.com.
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My initial reaction is a skeptical. Internet sources, even from multiple sites can be a fraud. There are numerous internet scams which are quite clever citing impressive results, utilizing terms, referencing what seem to be credible institutions. utilizing several websites so there are multiple sources of the "breakthrough". sometimes the institutions cited are credible but the product has no actual relationship. The scammers are getting increasingly sophisticated. Money to made. A worldwide market. An easy vehicle...the internet...and very difficult to track and get redress.
Those of us facing cancer and challenging medical conditions, especially some cancers with poor outcomes with limited or exhausted treatment options are desperate ducks...searching for hope.
Presto! A news report. . It started out with a news story and seemed credible and hopeful. Lucky it only cost me $70. Thanks. Hank
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Clarification: My bad experience was not in reference to the opportunity/development you cited. Hank
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http://www.genengnews.com/news/bnitem.aspx?name=26965488&source=genwire
one would think that this had already been known but it was not... this is important because any fundamental important thing science learns about the immune system and the very cells we are all worried about can help in many areas
Cancer’s Ability to Evade Immune System Illuminated
Nov 20 2007, 12:07 PM EST
GEN News Highlights
Regulatory T cells can reverse the role of macrophages, which are normally involved in causing inflammation, report scientists at King’s College London.
http://www.genengnews.com/news/bnitem.aspx?name=26965488&source=genwire
Regulatory T cells =T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system so that responses do not go haywire. Regulatory T cells come in many flavors, including those that express the CD8 transmembrane glycoprotein (CD8+ T cells), those that express CD4, CD25 and Foxp3 (CD4+CD25+ regulatory T cells or "Tregs") and other T cell types that have suppressive function. These cells are involved in closing down immune responses after they have successfully tackled invading organisms and also in keeping in check immune responses that may potentially attack one's own tissues
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Here are hundreds of peer reviewed articles on this filter that science has been working on over years, and having some success
http://scholar.google.com/scholar?q=Aethlon+Medical&hl=en&lr=&btnG=Search
http://scholar.google.com/scholar?q=Hemopurifier&hl=en&lr=&btnG=Search
smoothstone i must answer your concerns because i only post if there is valid proven science behind things
there are tons of huge advances in cancer treatment and many clinical trials, the last 1,10, 20, years has shown huge leaps and new clinical trials, are you near a big research university like UCSF or have you asked your doctor if there are any trials for your type of cancer, he may not know and you may have to find out and do some searching on the govt clinical trial website
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Thanks for the info. My skepticism is fueled by my loss of $70 sent via credit card in response to a scam involving news report, alleged experts giving testimony/credibility and quick product availability...
I am in SF with access to some clinical trials. A dilemma is that if you try one treatment now you often exempt yourself from future clinical trials of more promising treatments. In lung cancer, treatment options are beginning to expand beyond the chemo therapy radiation modes which are pretty tough side effectwise, and have shown limited efficacy for most folks. Hank.
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The Proprotein Convertase PCSK9, as a Potent Inhibitor of Hepatitis C Virus Replication
The Hepatitis C virus (HCV) is a worldwide leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, afflicting more than 180 million people worldwide. However, with current clinical treatment achieving viral clearance in only 50% of chronically infected patients, new treatment strategies for management of hepatitis C are urgently needed. Impeding advancements are some important mechanisms of HCV infection that are not fully understood, such as viral entry into hepatocytes. Recent focus has been on the tetraspan receptor CD81 and on the low density lipoprotein receptor (LDLR), which is known to play a part in HCV infection.
Proprotein Convertase PCSK9 plays a critical role in the regulation of lipid metabolism and cholesterol homeostasis through a reduction of the LDLR at the cell surface and the subsequent increase in circulating LDL-cholesterol in the blood stream.
We have identified PCSK9 as a very potent inhibitor of viral replication.
Results clearly indicate that Huh7 cells constitutively expressing PCSK9 are unable to sustain efficient HCV replication. The effect was even more pronounced when using PCSK9 chimeras harbouring an increased activity on LDLR and CD81 clearance from the cell surface. Significantly, the addition of purified soluble PCSK9 to the cell culture medium was also shown to prevent infection by HCV
quote from uventures.com
Knowledge Express, Pharma-Transfer, TechEx and Uventures,
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65% of adults have antibody to HSV-1
In homosexual and bisexual men with HIV infection, the rate of HSV-2 seropositivity is approximately 75%.
http://www.medscape.com/viewarticle/421019_4
Herpes Simplex Virus Infection
Human herpes virus infection is a common malady that is exacerbated by HIV infection. In the general United States population approximately 65% of adults have antibody to HSV-1 and 25% have antibodies to HSV-2.[58,59] HSV-2 behaves as a sexually transmitted disease with increased seroprevalence in post-pubescent adults. In homosexual and bisexual men with HIV infection, the rate of HSV-2 seropositivity is approximately 75%.[60,61]
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ok after reading this i think we have two very powerful concepts and discoveries here
first
"hematopoietic stem cells (HSC) - stem cells receive a lipid signal that enables them to exit into the thoracic duct. When the receptors on the stem-cell surface that detect pathogens become active, the cell’s ability to receive the lipid signal is blocked. The stem cells literally get stuck in the tissue, where they are then triggered to proliferate into immune cells,"
This could be analogous to why and how the strange fat build up occurs in viceral fat deposits, some lipid signal gone awry.-- not necessarily this lipid signal but one or another lipid signal
"hematopoietic stem cells (HSC) can divide and mature into immune system cells on the spot.
Scientists have known that a fraction of HSCs will sometimes migrate from the bone marrow into the bloodstream."
this could have an effect on why there is not a perfect correlation between VL, CD4 count etc
if there is a new just discovered part of the immune system that can pump powerful fresh versatile stem immune cells then this would have all kind of implications
anyone who is knowledgeable like the science guys and bio guys who post on here please add your comments-- how would this come into play in hiv disease and in the immune system
i recently read in another report that hair turns grey because the tiny stem cells at the base of the hair follicle die off or give out and they cant produce any new pigment cells -- this was a mystery for long time --
and i personally noticed that over the heart many men will get grey chest hair first in the area above and around the heart-- i made an assumption that this was because the tremendous strain and constant healing and repair that the heart must under go in all of us, uses up or burns out the stem cells that are in the chest hair follicals first --- just in same way that a childhood injury to the scalp can cause premature greying -- the chemical molecular healing that must occur constantly on the heart has a peripheral effect which is the stem cells in the hair follicles above the heart get effected too
questions -- would these newly discovered cells get involved in the attack against the cd4 cells, would that not be a strain on the system and the bone marrow that produces them, a constant
http://www.genengnews.com/news/bnitem.aspx?name=27325527&source=genwire
Scientists Find that Blood Stem Cells Are an Active Part of the Immune System
Nov 29 2007, 12:38 PM EST
GEN News Highlights
Harvard Medical School investigators found that upon encountering an invader, hematopoietic stem cells (HSC) can divide and mature into immune system cells on the spot.
Scientists have known that a fraction of HSCs will sometimes migrate from the bone marrow into the bloodstream. To understand why, they began by extracting lymph samples from the thoracic duct of a mouse, which routes the body’s excess fluids into circulation.
After screening, they discovered an extremely small population of blood stem cells. Further tests, which involved mice genetically engineered so that their blood stem cells could be detected through fluorescent microscopy, revealed that these cells were also scattered throughout visceral organs such as lthe iver, heart, and lungs.
“Taken all together, a picture developed suggesting that these cells migrated from the marrow and into the circulation where they would then leak out and enter the tissue,” says team leader, Steffen Massberg, M.D., a postdoctoral researcher and cardiologist. “After that, the thoracic duct would empty them back into the circulation, where they could re-enter the marrow.
“But the question was, why,” notes Dr. Massberg. “What exactly are they doing?” To figure this out, the researchers injected a bacterial endotoxin into the mouse tissue.
They found that after residing for a while in the organ tissue, the stem cells receive a lipid signal that enables them to exit into the thoracic duct. When the receptors on the stem-cell surface that detect pathogens become active, the cell’s ability to receive the lipid signal is blocked. The stem cells literally get stuck in the tissue, where they are then triggered to proliferate into immune cells, the scientists explain.
The paper will be published in the November 30 edition of Cell.
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it has been a month or two and no one posted anything on this
i see it as a big step forward
they are testing a new monoclonal antibody
can someone explain about drugs and monoclonal antibody
i heard that they use the monoclonal antibody to then later figure out what small molecule drug could do same thing but isnt as folded up and fragile as a monoclonal antibody which is a protein correct
this seems like a great step forward
treatment of chronic viral infections - why did no one post anything
first they used this new monoclonal antibody for melanoma cancer
now treatment of the first chronic viral infection they are trying it on
my feeling is it will take a cocktail of monoclonal antibodies to treat of chronic viral infection
because the immune system is so complicated
what are your thoughts
great , good , or ho hum
and why
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Genentech big into autoimmune diseases research research spending 50% of the company's sales
autoimmune diseases, they afflict some 23.5 million Americans and are so disruptive for victims that they cost the U.S. health-care system $100 billion a year—nearly double the economic burden of cancer.
http://www.businessweek.com/magazine/content/07_51/b4063000924207.htm?chan=technology_technology+index+page_top+stories
Genentech's research spending to 50% of the company's sales—more than twice what most drug companies spend on R&D. The resulting stream of hit drugs pushed Genentech's sales up from $1 billion to $9 billion since 1999, and the company swung from a $1 billion loss that year to profits of $2 billion in 2006. Genentech's market cap soared past $75 billion,
genetech is putting big push on autoimmune diseases this would could help us because any money spent by big player on immune system has to help us eventually
i am going to study what hiv papers are published by this giant firm in 2007 peer reviewed hiv papers science papers
now see what discoveries they are making in hiv this year
http://scholar.google.com/scholar?as_q=Genentech+hiv&num=100&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=&as_publication=&as_ylo=2007&as_yhi=2007&as_allsubj=all&hl=en&lr=
Results 1 - 100 of about 482 for Genentech hiv. (0.23 second 2007
here is a dec 5th 2007 article
HTLV-IIb reduces HIV infection http://bloodjournal.hematologylibrary.org/cgi/reprint/109/5/1792
----------------------------------------------------------------------------------------------------------------
Davide Zella INSTITUTE OF HUMAN VIROLOGY
The article of Pilotti and colleagues aims to elucidate the anti-HIV mechanism(s)
related to HTLV-II coinfection in intravenous drug users (IDUs). The authors
demonstrate spontaneous production in vitro of an isoform of MIP-1 (CCL3L1)
in PBMCs from HTLV-II–infected subjects, and this isoform was the major determinant
of anti-HIV activity in coinfected HTLV/HIV subjects, possibly due to
interference with chemokine receptor CCR5. Additional studies provide indirect
evidence that the mechanism should act at a transcriptional level.
First isolated in association with a rare form
of hairy cell leukemia,1 and subsequently
classified in 2 different subtypes (a and b),
human T-lymphotropic virus type II (HTLVII)
has been associated with several lymphoproliferative
manifestations, although its direct
role in causing a disease has never been
unequivocally demonstrated. Based on evidence
in vitro and epidemiologic studies, it has
been speculated that type a could exert a more
detrimental role interacting with the immune
system than type b.
HTLV-II has been shown to be endemic
among various American-Indian populations
in North America, in Panama, and in South
America. HTLV-II can be transmitted in 3
ways HTLV-II did not cause any
fast progression to acquired immunodeficiency
syndrome (AIDS) in IDUs, but on the
contrary it was surprisingly associated with a
delayed progression. It was only after the discovery
of chemokines as natural inhibitors of
human immunodeficiency virus (HIV) infection,
2 that the possible mechanism of
HTLV-II protective action started to be elucidated.
Indeed, an increased C-C chemokine
production in certain coinfected patients was
noted.3,4
The current article by Pilotti and colleagues
provides a better comprehension of
this mechanism. In fact, it appears that
HTLV-II infection triggers production of
CCL3L1, an isoform of MIP-1 that is primarily
responsible for protection (see figure).
This induction seems to act at a transcriptional
level, though the authors do not provide any
direct evidence to sustain this hypothesis. In
addition, other “protective” cytokines were
produced as a result of HTLV-II infection.
The effect was noted not only in stimulated
peripheral blood mononuclear cells
(PBMCs), but also in unstimulated cells. The
authors thus propose that HTLV-II confers a
protective state able to reduce susceptibility to
HIV infection.
More studies are needed to determine how
and why HTLV-IIb alters the cell programming
apparatus to induce production of CCL3L1,
protective cytokines, and a protective status
against HIV. Eventually, this might result in a
better understanding of the interactions between
the virus and components of the immune system.
It could also help in an understanding of
how to induce such a protective staus.
Genentech makes its first-ever acquisition - all 2 versions »
M Hollmer - Nature Biotechnology, 2007 - nature.com
... Tanner. Nor does he believe that the Tanox pipeline—including its HIV
drug candidate TNX 355—fits Genentech's strategy. Others
http://bloodjournal.hematologylibrary.org/cgi/content/full/109/10/4116
Indeed, the authors demonstrated profound perturbations in the levels of cytokines. They describe a vicious cycle, whereby activated cells are the source of cytokines that in turn activate new cells. This cycle may be embedded in a somewhat more general scheme including positive and negative feedback effects, as well as amplification of effector memory T cells (and of apoptosis) due to the rapid, transient proliferation and differentiation of activated cells2 (see figure). Thus, the higher proportion of lymph node T cells with effector-memory phenotype, reported here and elsewhere, may primarily be the result of increased turnover.
http://bloodjournal.hematologylibrary.org/cgi/reprint/109/11/4593
PD-1+ T cells: exhausted and premature? - all 2 versions »
L Su - Blood, 2007 - bloodjournal.hematologylibrary.org
... PD-1 up-regulation is correlated with HIV-specific memory CD8 + T-cell exhaustion
in ... Blood Online is supported in part by Genentech BioOncology and Biogen Idec. .
nhibition of HIV-1 entry by antibodies: potential viral and cellular targets
F Password - Journal of Internal Medicine, 2007 - Blackwell Synergy
... AIDSVAX B/B, AIDSVAX B/E, HIV gp120 vaccine – Genentech; HIV gp120 vaccine AIDSVAX –
VaxGen; HIV vaccine AIDSVAX – VaxGen. Drugs RD 2003; 4: 249–53. ...
Web Search
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/109/7/2978?ck=nck
Brief Report
HIV-1 infection and pathogenesis in a novel humanized mouse model
Liguo Zhang1, Grigoriy I. Kovalev1, and Lishan Su1
1 Department of Microbiology and Immunology, The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
The Rag2-{gamma}C double-knockout (DKO) mouse lacks T, B, and natural killer (NK) cells, and allows development of a functional human immune system with human CD34+ hematopoietic stem/progenitor cells (DKO-hu HSCs). Normal human T, B, and dendritic cells are present in peripheral blood, thymus, spleen, and lymph nodes. We report that both CCR5 and CXCR4 are expressed on
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2796.2007.01820.x
http://bloodjournal.hematologylibrary.org/cgi/reprint/109/3/854?ck=nck
CCR5 and HIV: December 5, 2007
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/109/8/3351?ck=nck
Here, we show that IDO mRNA expression is elevated in peripheral blood mononuclear cells (PBMCs) from HIV+ patients compared with uninfected healthy controls (HCs), and that in vitro inhibition of IDO with the competitive blocker 1-methyl tryptophan (1-mT) results in increased CD4+ T-cell proliferative response in PBMCs from HIV-infected patients. W
HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2, 3-dioxygenase in plasmacytoid … - all 3 versions »
A Boasso, JP Herbeuval, AW Hardy, SA Anderson, MJ … - Blood, 2007 - bloodjournal.hematologylibrary.org
... IMMUNOBIOLOGY. HIV inhibits CD4 + T-cell proliferation by inducing indoleamine
2,3-dioxygenase in plasmacytoid dendritic cells. Adriano ...
Vaccine-induced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines. However, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing antibody responses through vaccination has proven to be extremely difficult. The major targets for HIV-1 neutralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate receptor binding and entry. HIV-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including the masking of conserved regions by glycan, quaternary protein interactions and the presence of immunodominant variable elements. The primary challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers. Here, we describe neutralizing determinants on the viral envelope glycoproteins that are defined by their function in receptor binding or by rare neutralizing antibodies isolated from HIV-infected individuals. We also describe the nonvariable cellular receptors involved in the HIV-1 entry process, or other cellular proteins, and ongoing studies to determine if antibodies against these proteins have efficacy as therapeutic reagents or, in some cases, as vaccine targets to interfere with HIV-1 entry.
this book especially page 324, 325, 326 etc
have amazing overview of viral treatments now and in the future
http://books.google.com/books?hl=en&lr=&id=lxmyfSave4IC&oi=fnd&pg=PA323&dq=Genentech+hiv+%22Genentech+%22&ots=ekP701XFug&sig=7QEvIZz9o8HU7Qd5Fr-GRyXuA-o#PPA325,M1
esp. interesting is using Ig for anti virus
and colostrum
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From www.bloodjournal.org by on December 5, 2007. mRNA-rich microvesicles (MVs).
These observations3,4 also suggest that
MVs may transfer infectious particles such
as HIV and prions to other cells. They further
raise the possibility that exogenous
RNA and DNA modulate critical biologic
and pathologic responses when they are incorporatedinto
target cells. If so, then the
mechanisms that cells use for dynamic exchanges,
transfer events, and dialogs may be
even more daedal and intricate than currently
recognized, and if the specific mechanism
of stem-cell MV transfer of mRNA to
endothelial cells3 occurs in vivo, it may provide
a new pathway to angiogenesis in human
disease (see figure).
Cells use receptor-ligand interactions and endocrine, paracrine, and juxtacrine mechanisms to transmit signals to one another.
Deregibus and colleagues now report that information transfer between cells also occurs through horizontal transfer of
mRNA-rich microvesicles (MVs).
MVs are membrane blebs shed from the
surface of activated cells. Although
they were originally considered to be inert
cellular debris, it is now known that MVs
interact with cells through specific receptorligand
interactions.1 MVs also transfer receptors,
proteins, and bioactive lipids to
target cells.1 In this issue of Blood, Deregibus
and colleagues extend the functional
repertoire of MVs by showing that they are
vehicles for mRNA transport and the exchange
of genetic codes.
http://intl-bloodjournal.hematologylibrary.org/cgi/reprint/110/7/2219
From www.bloodjournal.org by on December 5, 2007.
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The Company is also in discussions with clinical investigators regarding the design and implementation of a second Phase 2 trial with new HspE7 in patients that are HIV-positive with low-grade CIN.
Montefiore Medical Center; William D. Kolton, M.D. of San Diego, California; Linda Roman, M.D. of the University of Southern California (USC); Michael L. Twede, M.D. of the Salt Lake Women's Center in Sandy, Utah; and Mark T. Saunders, M.D. at the Mt. Timpanogos Women's Healthcare/Physician's Research in Pleasant Grove, Utah.
http://freshnews.com/news/biotech-biomedical/article_41200.html
Nventa completes enrollment and initial dosing of second cohort in Phase 1 HspE7 safety trial
12/6/2007 @ 8:10 AM print this article - email to a friend - join our eNewsletter
Nventa Biopharmaceuticals Corporation today announced that the Company has completed enrollment and initiated dosing of the second cohort of patients in its Phase 1 dose escalation trial examining the safety of its lead candidate, HspE7, in patients with cervical dysplasia, a precursor to cervical cancer. HspE7 is an investigational therapeutic vaccine targeting human papillomavirus (HPV)-related diseases. Patients in this cohort have received the first of three immunizations of 500 mcg of HspE7 with 500 mcg of adjuvant.
In addition to safety and tolerability assessment, Nventa will also collect immunological data from these patients at the end of each cohort that may provide an early indication of potential efficacy of the compound. All patients will be typed for class I and II human leukocyte antigen (HLA) subtypes, and will be evaluated for cytokine responses, anti-HspE7 antibodies and cellular (T-cell) immunology.
Affiliations and investigators in this trial currently include the Montefiore Medical Center; William D. Kolton, M.D. of San Diego, California; Linda Roman, M.D. of the University of Southern California (USC); Michael L. Twede, M.D. of the Salt Lake Women's Center in Sandy, Utah; and Mark T. Saunders, M.D. at the Mt. Timpanogos Women's Healthcare/Physician's Research in Pleasant Grove, Utah.
Following successful completion of this Phase 1 trial, the Company anticipates launching a Phase 2 clinical trial with new HspE7 in patients with high-grade cervical intraepithelial neoplasia (CIN 2/3). The Company is also in discussions with clinical investigators regarding the design and implementation of a second Phase 2 trial with new HspE7 in patients that are HIV-positive with low-grade CIN.
About HspE7, Lead Product Candidate:
HspE7 is a novel therapeutic vaccine candidate for the treatment of diseases caused by the human papillomavirus (HPV), one of the most common sexually transmitted diseases in the world.
HspE7 is derived from Nventa's proprietary CoVal(TM) fusion platform, which uses recombinant DNA technology to covalently fuse stress proteins to target antigens, thereby stimulating cellular immune system responses. Heat shock proteins (Hsps), also known as stress proteins, are naturally present in the human body and play important roles in the immune system, including transporting substances within cells and activating cells of the immune system.
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http://forums.poz.com/index.php?topic=17566.msg223988#msg223988
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bim
the trial for the HPV pre-cancer vaccine is interesting - i just started Gardasil and have been wondering about its effectiveness on strains I or someone getting it might already have. have you heard anything about new studies on this?
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wow... this really *IS* "Bimazek's Research News" -- such chutzpah!
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Tim Horn set the thread up for him Philodendron.
MtD
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Thanks honey, I figured that out after I made that post :)
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Hopefully he'll keep his toys in his playpen. :)
MtD
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DNA vaccines have the potential to bypass inherent scientific obstacles of conventional vaccines that prevent their development for cancer and chronic infectious diseases such as HIV and hepatitis C. Pre-clinical data has indicated the ability of Inovio’s technologies to effectively deliver and significantly enhance the potency of such immunotherapies without the potential safety concerns of viral delivery systems.
Inovio Biomedical Receives Additional Milestone Payment from Merck Relating to Electroporation Delivery System for DNA Vaccines
Companies mentioned in this article:
http://freshnews.com/news/biotech-biomedical/article_41292.html
Vical
12/12/2007 @ 6:41 AM print this article - email to a friend - join our eNewsletter
“This is the second investigational DNA-based vaccine that Merck has advanced into clinical studies using Inovio’s proprietary electroporation delivery technology,” said Avtar Dhillon, MD, Inovio’s president and CEO. “Achievement of this milestone demonstrates Inovio’s ability to collaborate with large pharma partners to add value to their DNA-based vaccine programs.”
About Inovio’s DNA Vaccine Technology
DNA vaccines have the potential to bypass inherent scientific obstacles of conventional vaccines that prevent their development for cancer and chronic infectious diseases such as HIV and hepatitis C. Pre-clinical data has indicated the ability of Inovio’s technologies to effectively deliver and significantly enhance the potency of such immunotherapies without the potential safety concerns of viral delivery systems.
Inovio’s DNA-based immunotherapy products consist of DNA plasmids and electroporation-based DNA delivery systems. DNA plasmids are designed to express (produce) antigens that can induce an immune response specific to a cancer or infectious disease-causing organism. These plasmids are created synthetically and readily manufactured using well-established bacterial fermentation and purification technology. After a plasmid is delivered into muscle or tumor cells, production of the desired antigens may induce a preventive or therapeutic immune response against the intended disease. Inovio’s advanced electroporation devices facilitate delivery and expression of DNA vaccines to produce the desired antigens. Non-human primate and/or interim Phase I data delivered using Inovio’s DNA delivery systems have shown significantly enhanced antibody and T-cell immune responses relative to plasmid DNA delivered by other methods, suggesting the potential to provide better preventive or therapeutic effects against complex infectious diseases and cancers.
Inovio is able to deliver advanced DNA-based vaccines and immunotherapies, devices and know-how in this rapidly advancing field. The company is actively licensing its technology to pharmaceutical and biotechnology companies and supporting early stage clinical studies arising from its own research efforts or through academic collaborations.
About Inovio Biomedical Corporation
Inovio Biomedical Corporation (AMEX:INO), a leader in enabling the development of DNA vaccines using electroporation-based DNA delivery, announced today it will receive a $2 million milestone payment from Merck & Co., Inc. resulting from the filing of a second Investigational New Drug application to the US Food & Drug Administration by Merck for a DNA-based vaccine using Inovio’s MedPulser® DNA Delivery System. The milestone relates to Inovio’s collaboration and license with Merck initiated in May 2004 for the development of certain DNA vaccines. Further development of the product may lead to additional milestone payments and royalties to Inovio.
Inovio will receive this milestone payment for its contribution to the collaboration, which has so far demonstrated the high level of gene delivery and expression that is thought to be necessary for the induction of a therapeutic immune response. Merck has funded all clinical development costs of this candidate to date.
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http://www.sciencedaily.com/releases/2007/12/071213120945.htm
Clark said this evidence suggests that vaccines are likely ineffective against these diseases because Lewis sequences shut down the specific immune response that enables vaccines to work.
If aggressive cancers and pathogens are using the same system of universally recognizable markers to trick the immune system into 'thinking' they're harmless, we need to determine exactly how this interaction works," Dell said. "This is where we're planning to take this research next. Understanding how these markers work at a basic biological and chemical level could lead to new ways to treat or prevent cancers and these other diseases in the future."
"This work is creating an entirely new way of thinking about how we must combat viruses like HIV and aggressive tumor cells," Clark said. "We have literally spent billions of dollars developing vaccines for AIDS and cancer. However, the latest high profile HIV and tumor vaccine trials have been spectacularly unsuccessful, perhaps for some very good reasons. We must become more clever if we are ever going to solve the problems of cancer and AIDS."
This research is being published in the Dec. 14 edition of The Journal of Biological Chemistry.
Why Vaccines Directed Against Cancer, HIV Don't Work
ScienceDaily (Dec. 13, 2007) — Researchers from the University of Missouri and Imperial College London have found evidence suggesting why vaccines directed against the virus that causes AIDS and many cancers do not work.
In research spanning more than a decade, Gary Clark, associate professor of Obstetrics, Gynecology and Women's Health in the MU School of Medicine, and Anne Dell, an investigator at Imperial College London, found that HIV, aggressive cancer cells, H. pylori, and parasitic worms known as schistosomes carry the same carbohydrate sequences as many proteins produced in human sperm.
"It's our major Achilles heel," Clark said. "Reproduction is required for the survival of our species. Therefore we are 'hard-wired' to protect our sperm and eggs as well as our unborn babies from any type of immune response. Unfortunately, our results suggest that ...hiv-infected immune cells cause AIDS. The common thread is that each carries Lewis sequences.
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does this mean there is no hope down the pipeline?
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hi Bim, I just read an article on this myself ,very interested somehow my article got moved?
they want to attach these to dialysis machines to purify in hospitals next 2 years??/. google blood cleaner 2008
aethlon medical
I hope so then one can keep healthy longer and keep the viral load down from what I understand..
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http://www.natmedtalk.com/showthread.php?t=1840
looks a bit balky and big
i think that dr.'s feel that the new meds, and there are 120 new amazing meds in clinical trials and pre clinical trials as well as 3 new classes of meds just approved
i think dr.s feel that this will, these meds will take care of the hiv problem for vast majority
keep posting info
http://phx.corporate-ir.net/phoenix.zhtml?c=95588&p=irol-newsArticle&ID=1077924&highlight=
seems like gp120 is a nasty protein that hurts us produced by hiv
http://phx.corporate-ir.net/phoenix.zhtml?c=95588&p=irol-newsArticle&ID=1079395&highlight=
exosomes are produced by cancer and hurt people
http://www.nature.com/bjc/journal/v92/n2/full/6602360a.html
the parallel between cancer as a disease how it hides or confuses the immune system and
hiv as a disease how it hides or confuses the immune system are more and more true
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This is a double whammy good breakthru
two big breakthroughs
or 273 breakthroughs plus 1 super huge one and that one is incalculably huge...
breakthrough one...
basically they found 273 new ways to possibly attack HIV
breakthrough two ...
and at least one of them is so important it is the way that nature evolved a gene that is not susceptible to hiv, the famous long term non progress ors ...
rare individuals who do not progress to AIDS when they become infected with HIV. so this is especially cool because it should be possible if not easy to find a molecule a medicine that shuts off this gene that produces a protein that HIV loves and needs and we also know that this one in particular is not very important not very necessary because ALL long term non progressors have a mutation that removes this gene and removes this protein
i should suppresses or squelches this gene and this protein
and these humans don't seem to need that gene or that protein very much at all
They found the gene and protein involved with that...
the famous long term non progressors ...
http://www.webmd.com/hiv-aids/news/20080110/273-new-possible-targets-for-hiv-drugs?page=2
Experts Say Finding Is Major Advance continued...
One hopeful finding is that some people carry a mutant version of one of the proteins identified by the Elledge team, apparently with no harmful consequences. This mutant version of the protein, Haynes and colleagues recently learned, is found in some of the rare individuals who do not progress to AIDS when they become infected with HIV.
"One of the critical challenges of HIV research is to learn as much about the virus as we can, as fast as possible," Haynes tells WebMD. "Studies like this have the potential to move our knowledge forward quickly, which is important given the growing worldwide epidemic of HIV and AIDS."
The findings have broad significant beyond AIDS research. They show that the same techniques can be used to dissect the workings of other viruses -- and of cancers. Elledge says his team is now looking for the Achilles' heels of cancer cells.
Elledge and colleagues report their findings in the Jan. 10 issue of the online journal Science Express.
http://news.google.com/nwshp?hl=en&tab=wn&ncl=1126137345&topic=m
..........................
along with the many new things coming out i think this is one is the one final nail, albeit 5-9 years away from now to reach the market that will give many many many if not a vast majority a long long life.
the reason also is that these genes are necessary in many other viral diseases and now science knows that for Hepatitis and many other diseases these genes must be looked at so there will be many reasons to invest....
this is the best news i have read as far as basic research in the 20 months i have been poz
there have been other great best news that are brand new approved drugs and as poz mag or another mag said in this issue 2007 is as big a break thru year as 1996 for hiv drugs
but for basic research this is huge breakthru
my hats off to the smart and diligent scientists (i am a little shocked that this had not been done before but really it has only been 7 to 11 years that DNA RNA and human genome's sequencing existed and also the big big thing and reason why it happened now is it is only in last 1 or 2 or 3 that the cost of doing DNA RNA and human genome's sequencing fell from like five hundred million to one hundred thousand.
go it is basically happening at the right time it really could not have happened earlier
i mean geeze they had to do the DNA human genome's sequence first which they just finished a couple years ago before they could go back thru trial and error and test every gene again in a test tube one at a time to see if the proteins the gene make helped hiv grow fast.
anyway
hugs to everyone
this is a huge step forward
esp. the discovery for a gene (is it one or more than one) for non term non progressors
this is a nobel prize if you ask me
or should be.
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"One hopeful finding is that some people carry a mutant version of one of the proteins identified by the Elledge team, apparently with no harmful consequences. This mutant version of the protein, Haynes and colleagues recently learned, is found in some of the rare individuals who do not progress to AIDS when they become infected with HIV."
I have to agree with this one as being a huge discovery. If the mutant protein is in fact an independent factor needed by the virus to survive, and if the mutant virus truly causes no apparent harm to humans, this could be a very promising path for a therapeutic vaccine. Eyes on this discovery!
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http://news.google.com/nwshp?hl=en&tab=wn&ncl=1126137345
HIV Research Opens Up Potential Targets for Drugs
New York Times, United States - 7 hours ago
By DONALD G. McNEIL Jr. Using a new type of genetic screen, researchers at Harvard Medical School have identified 273 proteins that the AIDS virus needs to ...
"This is likely destined to be one of the best papers on HIV for this coming decade," said Robert C. Gallo, co-discoverer of the AIDS virus, who was not involved in the study. "I think it is terrific."
Gallo, who is director of the Institute of Human Virology in Baltimore, called the Harvard research "simply an elegant combination of modern molecular biology, new technology and bioinformatics that was used in a manner that has truly led somewhere."
Fauci, whose National Institutes of Health-affiliated laboratory also studies HIV's interaction with cells, said he is impressed by the strategy of selectively inhibiting cellular processes and then watching to see the effects.
"There is nothing that is completely new under the sun, but that is relatively ..." he said.
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"One hopeful finding is that some people carry a mutant version of one of the proteins identified by the Elledge team, apparently with no harmful consequences. This mutant version of the protein, Haynes and colleagues recently learned, is found in some of the rare individuals who do not progress to AIDS when they become infected with HIV."
I have to agree with this one as being a huge discovery. If the mutant protein is in fact an independent factor needed by the virus to survive, and if the mutant virus truly causes no apparent harm to humans, this could be a very promising path for a therapeutic vaccine. Eyes on this discovery!
in your post you say....
if the mutant virus truly causes no apparent harm to humans,
it is not
the mutant virus truly causes no apparent harm to humans,
it is a mutant human gene that causes all hiv viruses no matter what form or version or mutation to not be able to grow or change in the human who has the human gene mutation
this is very important to understand
if they can turn off this gene or suppress the protein then we all can live like
long term non progressors
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I meant mutant protein, correct. Thanks.
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http://money.cnn.com/news/newsfeeds/articles/marketwire/0353407.htm
this may be the first therapeutic vaccine that works, as you know the virus has a sugar coat and i guess a lipid coat that keeps the immune system from recognizing it, here they remove the lipid coat and the immune system has amazing results.... this is best vaccine results ever reported for HIV!!! therapeutic vaccine
led to an average 15.5 times viral load reduction in the treated animals. All 6 animals in the treatment arm of the study responded with drops in viral load in excess of 90%. While the study was not powered for statistical significance, it revealed an extremely strong trend of p=0.1, indicating the strong benefit of autologous delipidated viral vaccination in lowering viral loads in chronically-infected animals. Dr. James E.K. Hildreth commented on behalf of the study group, "The results of this study are terribly exciting and re-confirm an earlier outcome seen in a smaller group of immune-compromised animals. A viral load reduction in excess of 90%, to my knowledge, has never been seen before in other therapeutic vaccine studies. This treatment has the potential of introducing a whole new way of containing the pandemic of HIV." Lipid Sciences' Viral Immunotherapy is a broadly applicable platform technology that focuses on the removal of the lipid coatings from lipid-enveloped viruses utilizing the Company's proprietary delipidation technologies.
ps. this is not just animal results because the model of human hiv is close to this model it is a special animal model
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all topics from this link... please read full link to get more details
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/
Topic 1... HAART may over time help clear virus in some individuals
Tae-Wook Chun’s 10 questions you might have been afraid to ask at the 3rd Workshop on HIV Persistence During Therapy
Chun can’t find virus anywhere (including the gut), by any technique (RNA or DNA).
Is eradication possible?
Chun stated that five years ago, his answer would have been no. Now he is “cautiously optimistic in a subset of patients.” He has studied some individuals on long term ART who started relatively soon after becoming infected, and in one he can’t find virus anywhere (including the gut), by any technique (RNA or DNA). This individual has not tried stopping ART yet, however. Chun has also compared the proviral burden (amount of integrated HIV DNA) in small groups on long term ART (>7yrs) that started early vs. during chronic infection.
Topic 2... dual immunotherapeutic adjuvant/vaccination strategy may stimulate effective, long-term, immune-mediated control of persistent viral infections in humans
hopeful closing words of Brooks et al: “a similar dual immunotherapeutic adjuvant/vaccination strategy that alleviates immunosuppressive signals while boosting immunity may stimulate effective, long-term, immune-mediated control of persistent viral infections in humans, and may also be an adjuvant for primary vaccination.”
Consequently, blocking key suppressive factors could render ineffective vaccines more efficient at improving T cell immunity, and thereby allow immune-mediated control of persistent viral infection.
Souping Up Therapeutic Vaccines
Two new papers in the advance online section of the Journal of Experimental Medicine report that blocking immunosuppressive signals can give therapeutic immunization a boost. The studies follow on from work covered on the blog previously in which the IL-10/IL-10 receptor and PD-1/PD-L1 signaling pathways were identified as key contributors to viral persistence in the mouse model of chronic infection with lymphocytic choriomeningitis virus (LCMV).
In the first paper, David Brooks and colleagues from Mike Oldstone’s laboratory at Scripps show that combining DNA vaccination with an antibody blocking the IL-10 receptor leads to improved LCMV-specific CD4 and CD8 T cell function and accelerated clearance of the virus from chronically infected mice. In the second paper, Sang-Jun Ha and a team from Rafi Ahmed’s lab at Emory University report that immunization with a vaccinia vector encoding a single CD8 T cell epitope from LCMV also accelerates viral clearance when combined with an antibody blocking PD-L1 (the ligand for the molecule PD-1). The vaccine had no effect when given alone. In addition, these researchers demonstrate an effect of the vaccine plus PD-L1 blockade in mice transiently depleted of CD4 T cells, suggesting that the approach might have an impact in settings of CD4 T cell deficiency.
Both groups conclude by citing each other’s work and noting that, taken together, the results indicate that immunosuppressive signaling in chronic infection may explain the disappointing results of most therapeutic vaccination studies conducted to date. The authors also argue that their data point toward new strategies for boosting the impact of therapeutic immunization. In the hopeful closing words of Brooks et al: “a similar dual immunotherapeutic adjuvant/vaccination strategy that alleviates immunosuppressive signals while boosting immunity may stimulate effective, long-term, immune-mediated control of persistent viral infections in humans, and may also be an adjuvant for primary vaccination.”
The Journal of Experimental Medicine
Published online 10 March 2008
doi:10.1084/jem.20071948
Topic 3-- immunologist Mark Connors. Over the years, Connors has studied HIV-specific immune responses and authored many articles reported in the literature. In 2002, however, he identified HIV-specific CD8 T cell proliferation as a potentially important correlate, a finding several other research groups have now confirmed. At the summit, he cited additional assays his lab is working on, and expressed confidence that robust and broadly applicable correlates of immunological control are within striking distance. Furthermore, he also cited the fact that several Merck vaccine recipients who became infected in the STEP trial and carry the favorable immune response gene HLA B*57 are controlling their viral loads to undetectable levels. Initially, this was assumed to be an HLA B*57 effect but Connors argued that the frequency of the occurrence is far higher than would be anticipated in the absence of immunization, suggesting that it reflects an interaction between the vaccine and the favorable HLA allele akin to that seen in Merck’s now notorious SIV challenge studies, in which only immunized macaques bearing the Mamu A*01 allele (the B*57 equivalent) showed significant viral load reductions. The implication is that while the Merck vaccine was far from optimal, it may have been able to enhance the HLA B*57 effect. If this finding actually holds up, it may offer additional validation of the SIV/macaque model and it would also strengthen the argument for developing improved immunogens with the potential to achieve this outcome in people lacking HLA B*57.
Topic 4 Genetic Associations with Control of HIV Replication
HCP5 might somehow have a direct anti-HIV effect
HCP5 is also an endogenous retroviral element (a part of the human genome derived from an ancient retroviral infection which gained access the human germ line by infecting an egg or sperm cell) and so Goldstein initially speculated that the SNP in HCP5 might somehow have a direct anti-HIV effect. At CROI, he reported that studies in which the SNP-containing version of HCP5 was overexpressed in cells showed no inhibition of HIV replication, suggesting that the SNP is mediating its effect via other means (exactly how is under investigation).
Genetic Associations with Control of HIV Replication
At the recent CROI meeting, David Goldstein from Duke University gave a plenary presentation on genetic determinants of viral load set point in HIV-infected individuals. Their approach involved analyzing a staggering 500,000 different single nucleotide polymorphisms (SNPs) present in the human genome to see if they were associated with lower viral load set points . . The first was a SNP in a gene called HCP5. This is linked to an immune response gene called HLA B*5701 which is well known to be over-represented among HIV-infected long-term non-progressors (HLA B*5701 makes a receptor on CD8 T cells which appears particularly good at recognizing HIV epitopes). However, HCP5 is also an endogenous retroviral element (a part of the human genome derived from an ancient retroviral infection which gained access the human germ line by infecting an egg or sperm cell) and so Goldstein initially speculated that the SNP in HCP5 might somehow have a direct anti-HIV effect. But because HIV’s Nef protein is known to cause a reduction in HLA-B molecules on infected cells (as a means of escaping the immune response), Goldstein’s hypothesis is that the SNP he has identified causes more HLA-C molecules to be expressed, thereby making it easier for CD8 T cells to identify HIV-infected cells. He is currently collaborating with Andrew McMichael at Oxford University to measure the effect of the SNP on HLA-C expression.
To give a sense of how a combination of genetic factors can have a profound impact on HIV disease progression, Goldstein showed an analysis that included the SNPs in the HCP5, HLA-C, and ZNRD1/RNF39 genes and two other known favorable genetic polymorphisms in CCR5 and CCR2 genes (CCR5Δ32 and CCR2 V64I). HIV-infected individuals with no favorable mutations in any of these genes showed an average time of less than two years from infection to a CD4 T cell count of less than 350. In contrast, people with one or two favorable mutations in at least four of these genes did not experience a CD4 T cell decline to this level for an average period of more than eight years.
Goldstein’s group is now embarking on an effort to uncover genetic associations with the magnitude of antibody responses generated against a vaccine, using data from the North American efficacy trial of AIDSVAX. This is a potentially important area of study because the ability of an individual to generate a high titer antibody response was correlated with reduced susceptibility to HIV infection in the trial cohort. Some researchers have suggested an analogy with the association between the magnitude of anti-Ad5 antibody responses and susceptibility to HIV infection seen in the placebo group of the recent Merck vaccine trial, so Goldstein’s work may have the potential shed light on that mystery also. Another important area of ongoing study mentioned by Goldstein is an analysis of genetic associations with viral load set point restricted to African American individuals.
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You already have a thread (http://forums.poz.com/index.php?topic=15762.0) for this stuff
MtD
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Bim,
I merged your threads. Don't keep starting new ones, OK? Thanks.
Ann
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Summit on HIV Vaccine Research and Development
was recently held and researchers from all over world met
http://www.macrovolt.com/live/dgi_032508/
I have just spent good parts of the last 3 days watching this video broadcast of the top world vaccine specialists researchers for hiv it is over 6.5 hours long and sometimes i had to go over what someone said 2 times to fully absorb all the complicated stuff
basically there is much to report here
obviously the news mis reported some of it
but the big things are
there is not enough money for any of the HIV vaccine research even with the big gates grant, that even the primate labs in new england are having trouble paying
heating bills because of the high costs of fuel, that the congress is not putting up enough money and there is a vast vast undersupply of money on this problem
this was shocking to me because i thought there was enough money in preventative and therapudic vaccine research so perhaps activism can help
other topics
they have a very very good animal model which is almost exactly similar to human hiv to test any new vaccine ideas but it is expensive to keep breed the animals, but human trials are only way to truly see if a new idea for vaccine will really work even though animal models are very good
at the hour of 5:06 the video made me cry and tear up when the emory director said that he and his staff personally called all 130 vollenteers to tell them of the merck failure
and the vollenteers said universally, "when can we vollenteer again to help" -- imagine the scientists called to tell them that some vollenteers were made more susseptable
and these wonderful selfless individuals want to help all of mankind and want to vollenteer again even in the face of the risks i am still choacked up just reading this above
other things said in the 5 hour summit
the guy who invented the malaria vaccine, the cholera vaccine and many others had interesting things to say about how hiv is yes different and harder but not that much different and not that much harder and that it is still possible to make the vaccine and hey malaria vaccine, the cholera vaccine was hard to figure out too
there is not enough money to keep the young new researchers in the field
that if you treat someone with HAART within the first days of infection then give a vaccine this was something unique therapudically
that many many new ideas and parts of the virus and new basic science needs to be learned
that no scientist really know exactly how ANY existing vaccine works exactly for any disease so they need to study this in detail in the immune system,
that they are getting close or at least there is many new avenues and ways to design a vaccine that needed to be tested in humans asap
that there is lots of vollenteers so human vollenteers are not a problem
that well many many detailed scientific ideas and explainations that you have to watch the whole thing to see it, but basically there are lots of ways to deliver parts of the hiv coat envelope, proteins, insides, etc and also many new ways to stimulate the immune system in many different ways that need to be invented and thought of and tried
that perhaps soneone could still just stubble upon an idea or a solution and wow suddenly we would have a vaccine for hiv and it may come from many areas of research not just pure hiv research
that bruce walker at harvard is a genius because he is looking at early infection and also at elite controllers but even he had to go to private money sources to fund what seems to me so obvious -- figure out how the elite controllers immune system controls infection without meds and replicate it
that even harvard isn't helping enough with money for hiv research if they have a 92 billion endowment and one of their top researchers had to go begging to get money to study this... my opinion ... if you went to harvard, yale, emory, or UC or any big medical research university try to get involved and see if more money can be put into hiv research please
that many brilliant people all of usa and world are workign very very hard but all the easy things for vaccines for hiv have been tried and all have failed
that there are a few very great giants minds in the field and they are like gods with thier discoveries and ideas and research,
that there is so so so much that the science does not understand about how hiv hurts the immune system and also how the immune system works itself
that science must come up with many new vaccine ideas and then has to select only the best ideas for trials in animals and then people
that smaller trials are better and faster with smaller groups of people
i strongly oppose the AHF in their call for slowing hiv vaccine trials that was a big mistake
many new dev. in hiv vaccine research two papers in euro vac dna prime -- many promising signs
there was a difference in protection with a vaccine in protecting circumsized and uncircumsized men
prime boosted vaccines using many different vectors to insert the genetic material
cultivate the new young investigators
come up with new ideas
primate models quite good according to gallo
one hurdle to vaccines is science must maintain antibody response continually for first many weeks, but they cant figure out how to do that -- i personally never understood why giving same vaccine 5 times would not help with that question
someplace called OTC talked about by gallo has billions of dollars and a rotating chairmanship sometimes to family memeber and he felt they should put more money into vaccine research
us army is doing hiv vaccine research according to gallo
they have vaccines that reduce somewhat viral load but it does not last but that it increases survival so that they are getting closer
one guy said we are not there and we are not close we need lots of basic science to figure out how to make a vaccine
discovery innovation
we need to be evolutionists... what can we learn from primates who get siv but live with it with out getting sick he said
we will not stop hiv vaccine research even though ahf asked us to stop, not only will we not stop it we will not even consider stopping, not only will we not stop we will try to increase the budget for it wherever possible
there is competition between research institutes, universities, private biotech companies, us army, and other usa and intl orgs all working on vaccine research and many called on coordinated efforts and more disclosure of who is working on what so that a new solution to vaccine is found faster safer and all agreed they must work leaner and with tight budgets
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Giant new discovery
see DIAGRAM HERE
http://tagbasicscienceproject.typepad.com/.shared/image.html?/photos/uncategorized/2008/01/10/brassimage.jpg
Giant new discovery I have been wanting to post this but have been out of town 4 months.
Probing HIV's Dependence Factors on Host cell Proteins
in my opinion, This is, (and I have been following HIV research and knowledge for 27 years since an MD/PhD/Vet researcher told me in 1981 that this new disease was caused by retrovirus just like in cats, he was one of first in world to guess this... ) in my opinion, This is.... drum roll
... this new discovery is the largest most important discovery in the history of any disease and in the history of HIV research. I believe. I hope the editors of this site will give it the attention it deserves. No other time in history has siRNA genetic analysis (which is brand new tool) used to find ALL the genes and proteins that a disease uses.
Never before has it been possible to see every gene and every protein that a disease process uses. This came about because of the love and hard work of clinical scientists who work with real people who have hiv.
The most exciting and important discovery is the diagram of all 273 genes and proteins that HIV hijacks to reproduce itself. See above diagram. This is it, there is no other genes or proteins they tested EVERY single human gene to see if hiv needed it to replicate.
This diagram represents one CD4 cell. This shows the actual paths and life cycle of HIV. The amazing part is that the part that is in GREEN was all that science knew before this discovery by HARVARD. EVERYTHING ELSE that is not green is new.
BTW all the present hiv meds work on only the pathways of the GREEN genes.
All the other proteins and genes that HIV hiJACKS in red or black paths or blue are NEW and never known before.
How they found all these is a miracle of new research techniques and they now know more about hiv life in a cell than any disease in the history of the world. Harvard and bruce walker are the geniuses behind all this and they will most definately deserve and win the nobel prize for this in my humble opinion.
What this means is that meds can be designed to dail down to lower the expression of one or more of these genes just like protease inhibitors or Nukes or non nukes reduce a cell process and thus halt hiv
but it is even more exciting because science believes that some of these genes can be reduced say twenty percent and this will turn off completely the production of HIV but not turn off the CD4 cell itself.
So that is exciting. How they did it..
"The researchers used an approach that involves blocking the activity of known human genes using small slices of RNA called small interfering RNAs (siRNAs). A staggering 21,121 pools of four siRNAs per gene were employed in the study, ultimately revealing 273 host proteins necessary for efficient HIV replication (the researchers have dubbed them "HIV dependency factors" or HDFs). Thirty-six HDFs comprise previously reported factors such as the CD4 and CXCR4 proteins. One identified protein, ZNRD1, was also implicated in a recent study of genomic associations with viral load set point in people with HIV (mutations in the gene for ZNRD1 were associated with slow progression) So much data was generated that much of it is not in the paper but in the supplemental online material that accompanies it. The authors also offer a schematic that gives a sense of the complex theater of virus-host interactions.."
supplemental online material --- i read this material it or skimmed it and it is incredible, and is tens of hundreds of pages of exactly what each of these genes does in the cell and the body it is complete, many of these genes science does not even know what they do in humans but they included the same gene and they knew what the gene does in other species
this is the diagram of the CD4 cell, first notice the famous green paths, all green is what was already known about hiv
notice the cd4 receptor at the top, follow the green line down into the cell into the nucleus,
notice transcription and integration -- this is the part that we all learn when we take a hiv meds for beginners class -- where the nukes and non nukes work, i cant find the protease enzyme on here but it must be there somewhere does anyone know the gene name for protease enzyme
HDFs stands for HIV Dependence Factors which are proteins or genes basically
remember that everything that is red, blue or black is new info new discoveries only weeks old
everyone of these can be target of new meds, new gene therapies or new vaccines.
http://tagbasicscienceproject.typepad.com/.shared/image.html?/photos/uncategorized/2008/01/10/brassimage.jpg
see this diagram and study it
if you have any question please post it here.
here is some more reports on this discovery in press
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/01/probing-hivs-de.html
http://www.google.com/search?hl=en&q=+hiv+dependency+factors&btnG=Search
http://www.citeulike.org/user/zwang/article/2219289
http://www.health24.com/news/HIV_AIDS/1-920,43677.asp
http://sbaminbeta.blogspot.com/2008/01/hope-survives-hiv-dependency-factors.html
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wow that is amazing data....great post.
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Good News- The sooner this translates into new drugs & gene therapies the better!
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Giant new discovery
see DIAGRAM HERE
http://tagbasicscienceproject.typepad.com/.shared/image.html?/photos/uncategorized/2008/01/10/brassimage.jpg
Giant new discovery I have been wanting to post this but have been out of town 4 months.
Probing HIV's Dependence Factors on Host cell Proteins
in my opinion, This is, (and I have been following HIV research and knowledge for 27 years since an MD/PhD/Vet researcher told me in 1981 that this new disease was caused by retrovirus just like in cats, he was one of first in world to guess this... ) in my opinion, This is.... drum roll
I think there is a specific thread that discussed this same subject some time ago:
http://forums.poz.com/index.php?topic=18308.0
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The practical application of this experiment is clear and crucial: A method to prevent HIV/AIDS could be devised from these findings. Infecting a person with measles is out of the question, but a new type of vaccine could be created that would give immunity to measles as well as HIV. The researchers are already well underway with further research, exploring other interactions of the HIV virus.
Measles virus slows progression of HIV infection
http://media.www.jhunewsletter.com/media/storage/paper932/news/2008/04/03/Science/Measles.Virus.Slows.Progression.Of.Hiv.Infection-3301387-page2.shtml
4-4-08
Scientists are using the world's most powerful computer to design drugs that could prevent HIV infection.
http://ukpress.google.com/article/ALeqM5hIMe8w-LeXTvfVaFYH-1DF-jNdJw
Jason Crain, IBM professor of physics at the University of Edinburgh, said: "The idea is to try and inhibit infection by the HIV virus rather than treat already infected cells so one of the strategies for doing that is to design molecules that will attach to the important parts of the virus and inhibit the initial viral fusion events.
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I did a search on all new hiv papers in 2008. There are 5000 so far. These dozen stood out when i reviewed the first 500 abstracts. 2008 science papers on hiv
http://scholar.google.com/scholar?q=hiv&num=100&hl=en&lr=&as_ylo=2008&as_yhi=2008&as_subj=med&start=300&sa=N
HAART lowers Viral Burden in the Lungs
Effect of Highly Active Antiretroviral Therapy on Viral Burden in the Lungs of HIV-Infected Subjects
http://www.journals.uchicago.edu/doi/abs/10.1086/523766
Conclusion. HAART is associated with a significant decrease in the pulmonary HIV burden and a return of alveolar cellular constituents to normal. Background. Human immunodeficiency virus (HIV) is readily detectable in the lungs of infected subjects and leads to an accumulation of CD8+ lymphocytes in the alveolar space. Although highly active antiretroviral therapy (HAART) is effective in reducing viremia, less is known about its effect on tissue compartments. The AIDS Clinical Trials Group Protocol 723 Team evaluated the effect of HAART on lung viral load and cellular constituents.
Journal of Infectious Diseases 2008;197:109–116
© 2008 by the Infectious Diseases Society of America. All rights reserved.
MAJOR ARTICLE
2008 Jan;180(1):21-9. Epub 2007 Nov 16.Click here to read Links
Magnetic resonance imaging findings of the brain in adult HIV and AIDS patients]
http://www.ncbi.nlm.nih.gov/pubmed/18008191
ascorbic Acid: Biologic Functions and
Relation to hiv
http://jnci.oxfordjournals.org/cgi/content/citation/83/8/547
The effect of ascorbate on human immunodeficiency virus
(HIV) replication was described by Dr Raxit Jariwalla (Linus
Pauling Institute, Palo Alto, Calif). In chronically infected T
lymphocytes exposed to high but nontoxic levels of sodium as-
corbate, reverse transcriptase activity was reduced by more than
99%. Levels of p24 HIV core antigen in the culture supernatant
were reduced by 90%. In acutely infected cells, ascorbate
reduced syncytium formation by 93%. The continuous presence
of ascorbate was necessary for HIV suppression. Ascorbate did
not inactivate extracellular virus. Under the same conditions,
there were no detectable inhibitory effects of ascorbate on
growth, metabolic activity, or rate of protein synthesis in unin-
fected T lymphocytes.
Future HIV Therapy
March 2008, Vol. 2, No. 2, Pages 99-104
(doi:10.2217/17469600.2.2.99)
http://www.futuremedicine.com/doi/abs/10.2217/17469600.2.2.99
Challenges facing the US HIV/AIDS medical care system
Journal of Infectious Diseases 2008;197:S34–S7
© 2008 by the Infectious Diseases Society of America. All rights reserved.
Stigma in the Time of Influenza: Social and Institutional Responses to Pandemic Emergencies
http://www.journals.uchicago.edu/doi/abs/10.1086/524986
Ron Barrett1 andPeter J. Brown2 1School of Nursing and 2Department of Anthropology, Emory University, Atlanta, Georgia
http://www.ncbi.nlm.nih.gov/pubmed/18190281
No patient was receiving highly active antiretroviral therapy before presentation with PCP, and none began highly active antiretroviral therapy during treatment of PCP. CONCLUSIONS: Mortality risk factors for PCP were identifiable at or soon after hospitalization. The trend towards improved outcome after June 1996 occurred in the absence of highly active antiretroviral therapy. BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) remains the leading cause of opportunistic infection among human immunodeficiency virus (HIV)-infected persons.
Apoptosis and HIV Infection: About Molecules and Genes
http://www.ingentaconnect.com/content/ben/cpd/2008/00000014/00000003/art00005 Abstract:
During the evolution, the immune system has developed several strategies to fight viral infections. Apoptosis, autophagy and necrosis are different types of cell death that play a main role in the interactions between infective agents and the host, since they are often important defence mechanisms that have to avoid the spreading of the infection. In turn, viruses have evolved numerous ways to evade the host immune system by influencing the behaviour and functionality of several components. HIV infects and kills CD4+ T helper lymphocytes, preferentially those that are antigen-specific, but also encodes proteins with apoptotic capacities, including gp120, gp160, Tat, Nef, Vpr, Vpu, Vif and, last but not least, the viral protease. This latter protein can kill infected and uninfected lymphocytes through the action of several host molecules, mainly members of the tumor necrosis factor family, or via the mitochondrial apoptotic pathway. The proinflammatory state that is characteristic of both the acute and chronic phase of HIV infection facilitates cell death, and is an additional cause of immune damage. Potent antiretroviral drugs that are largely use in therapy can reduce apoptosis by different mechanisms, that not only include the diminished production of the virus by infected cells and the subsequent reduction of inflammation, but also a direct action on the viral protease. The role of the host genetic background is finally crucial in understanding the process of cell death in HIV infection.
study of those terrible times before haart...
when there was no treatment http://aje.oxfordjournals.org/cgi/content/abstract/140/8/747
The median time from HIV seroconversion to AIDS was 8.3 years, that from HIV serocon version to death was 8.9 years, and that from AIDS to death was 17 months. The authors evaluated HIV disease progression with respect to demographic, clinical, and behavioral cofactors. Younger age and use of prophylaxis against Pneumocystis carinii pneumonia were significantly related to slower progression from seroconversion to death.
Can the New Humanized Mouse Model Give HIV Research a Boost?
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050013&ct=1
Barbara L. Shacklett From the perspective of a basic scientist searching for improved animal models in which to study human disease, the present study represents a clear advance in the field. However, given the uncertainties that remain, the BLT mouse is unlikely to replace the SIV model for studying pathogenesis and transmission. At this stage, the most prudent approach is to consider the new humanized rodents and the more established, nonhuman primate models as complementary systems, both of which can yield useful information but neither of which is infallible. Infection of rhesus macaques with simian immunodeficiency virus (SIV) has provided an excellent nonhuman primate model for studying HIV pathogenesis (reviewed in [3]). SIV is closely related to HIV on a molecular level, its replication may be inhibited by many of the same antiretroviral compounds, and it induces an acquired immunodeficiency syndrome (AIDS) that mimics human AIDS in many important respects.
Physiologic growth hormone (GH) replacement appears to be beneficial in patients with HIV-associated …
I Weekly - Inpharma Weekly, 2008 - inpharma.adisonline.com
... Physiologic growth hormone (GH) replacement appears to be beneficial in patients
with HIV-associated lipodystrophy,.
What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?
D Grover, A Copas, H Green, SG Edwards, DT Dunn, C … - Journal of Antimicrobial Chemotherapy, 2008 - Br Soc Antimicrob Chemo http://jac.oxfordjournals.org/cgi/content/abstract/61/3/705... What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?
Blood and Guts and HIV: Preferential HIV Persistence in GI Mucosa.
S Yukl, JK Wong - J Infect Dis, 2008 - ncbi.nlm.nih.gov
J Infect Dis. 2008 Feb 8; [Epub ahead of print], Blood and Guts and HIV:
Preferential HIV Persistence in GI Mucosa. Yukl S, Wong JK. http://www.ncbi.nlm.nih.gov/pubmed/18260765
What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?
D Grover, A Copas, H Green, SG Edwards, DT Dunn, C … - Journal of Antimicrobial Chemotherapy, 2008 - Br Soc Antimicrob Chemo ... What is the risk of mortality following diagnosis of multidrug-resistant HIV-1? ... Keywords:
MDR HIV-1 , genotypic sensitivity score , antiretroviral therapy. . http://jac.oxfordjournals.org/cgi/content/abstract/61/3/705
MDR HIV-1 , genotypic sensitivity score , antiretroviral therapy. ...
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http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20080413.094508&time=11%2021%20PDT&year=2008&public=0
Sangre de Drago ("Dragon's blood" or Croton lechleri), a plant with a blood-like sap (properly called "latex") that has been used by indigenous people for centuries to treat wounds, diarrhea, stomach problems, and other ailments (Jones 2003.) Shaman's researchers isolated and purified the main component from the latex, named "crofelemer," and formulated crofelemer into standard oral medication. The company produced a supplement called "Normal Stool Formula" that was widely used in the HIV community in the 1990s to successfully treat diarrhea. "It was our best seller for diarrhea," said Fred Walters, founding director of the Houston Buyers Club, a Houston-based non profit that provides supplements at cost to people with HIV nationwide. "We were sad to see Shaman close its doors due to financial difficulties back then, so we are glad to see Napo Pharmaceuticals acquiring the rights for the pharmaceutical-grade of the product for new research and potential FDA approval," added Mr. Walters. "In our country and most other western countries, there are only two anti-diarrhea medications, both approved over 30 years ago and both work about the same way -- they slow or stop the movement of the gut. Crofelemer works differently and we see an exciting opportunity to study crofelemer for HIV-associated diarrhea and many other diseases where diarrhea is a major, sometimes fatal symptom of other infections," said David Golman, PharmD, Senior Director of Clinical Operations of Napo Pharmaceuticals. An estimate by the World Health Organization suggests that worldwide, everyday 6,800 children die from diarrhea and its complications (Guerrant 2002.) "Clearly, there is the need for a more effective and widely available treatment for diarrhea," added Dr. Golman. Diarrhea associated with HIV infection is still very much an issue to many. In a survey performed by POZ magazine in September 2007 with a total of 941 responders, 21 percent said that side effects were the primary reason that they switched antiretroviral regimens in the past. Diarrhea, nausea and vomiting were the number one side effects that make a person switch meds. In a recent prospective study of 163 HIV+ patients performed by Dr. Uzma Siddiqui, 28.2 percent of patients reported having 3 or more bowel movements per day but only 14.1 percent reported use of anti-diarrheal medications (Siddiqui 2007).
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Bim,
I merged your threads yet again. How many times do we have to ask you to keep your research articles on one thread? ::)
Ann
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ZNRD1 nuclear pore protein ZNRD1
this is the gene that LONG TERM NON progressors have or dont have that makes them
LONG TERM NON progressors This was just discovered by harvard and emory univ. last month feb 2008
So i am doing some digging and reading of all articles about this ... nuclear pore protein znrd1
the good news is the chinese are really working on this at the Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. this could lead to a discovery of a medicine that would suppress this protein would halt hiv and everyone would be LONG TERM NON progressors!!!!
http://www.google.com/search?hl=en&q=nuclear+pore+protein+znrd1&btnG=Search
http://www.natap.org/2008/HIV/011408_04.htm
Science this week explains, that's where HIV's complexity becomes abundantly apparent. The findings also spotlight intriguing, novel drug targets. "This is destined to be one of the key HIV papers of this decade, if not longer," says Robert Gallo, who heads the Institute of Human Virology in Baltimore, Maryland, and did landmark studies that tied HIV to AIDS. Specifically, they took human cells and effectively short-circuited every known gene, one at a time, and then tested whether HIV could establish an infection and copy itself. Elledge and co-workers contend that HIV would have more difficulty escaping drugs that interfere with HDFs. True, HIV could evolve the capacity to copy itself without one of these factors, but that's a much more difficult task for the virus than mutating to prevent a drug from binding to a viral enzyme. On the flip side, human proteins don't mutate with anywhere near the ease of viruses, which makes it less likely that an HDF would develop drug resistance. Our screen found ZNRD1 depletion inhibited HIV (table S2). This suggests that variants in other HDFs might modulate HIV infection and drugs inhibiting their functions may prove protective.
Suppression of the cell proliferation in stomach cancer cells by the ZNRD1 gene
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WBK-4CXDNDG-4&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ccc5b2f900b13086afdf2c3dc3ef1012
Zinc ribbon domain-containing 1 (ZNRD1), a transcription-associated gene Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, People’s Republic of China
Received 14 June 2004. Available online 22 July 2004.
further validate ZNRD1 as a potential therapeutic target in gastric cancer.
i am looking at the history of ZNRD1 discoveries
it looks like they are already treating and perhaps curing stomach cancer with monoclonal antibodies that are ZNRD1 --Suppression of the cell proliferation in stomach cancer cells by the ZNRD1 gene -- remember that a monoclonal antibody can be a medicine or it can be a proof that a smaller simpler molecule, a drug, can be found that has the same 3D profile as the antibody
CHINA HAS A MONOCLONAL ANTIBODY ALREADY AGAINST ZNRD1 gene/PROTEIN
THIS IS VERY VERY GOOD NEWs this means they can immediately start experiments and they already have the
key shape, the monoclonal antibody for znrd1 they could even use this MONOCLONAL ANTIBODY as a medicine against hiv so trials of that will be conducted no doubt... after the harvard and emory discoveries of feb 2008!!!
http://www.liebertonline.com/doi/abs/10.1089/153685904322772042?cookieSet=1&journalCode=hyb.2
Liu Hong
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Yumei Zhang
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Shuang Han
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Jin Wang
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Yongquan Shi
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Yanglin Pan
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Na Liu
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Xiaoyin Zhang
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Daiming Fan
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
this is why i say that china will discover the cure and they will become even richer than they already are
i listed all thier names because they deserve the recognition and it is interesting to see the vastness of the country, i mean where is Xi'an and who are all these people, my point is when you have a billion and some are researchers in china some are at oxford and some are at top univ. in usa something good as got to come of it...
this i have no idea.. i am not a genetist, any bio gene experts how does this all relate
http://www.t1dbase.org/page/Locus/display/?loc_id=170
The C-terminal domain of TAP interacts with the nuclear pore complex and ..... We have named this gene ZNRD1 for zinc ribbon domain-containing 1 protein . ...
http://www.bionewsonline.com/t/1/fungi_yeast_p.htm
ZNRD1 (zinc ribbon domain containing 1)
IdentityOther names HTEX-6 MGC13376 Rpa12 hZR14 tctex-6Hugo ZNRD1 Location 6p21.3
http://www.antibodies-online.com/antibody/190724/At3g25940+transcription+factor+SII+TFIIS+domain+containing+protein++/
Peptide conjugated to a carrier KLH. Peptide has been chosen from Arabidopsis At3g25940 protein, which is a subunit of the Nuclear RNA polymerase A, also called RNA polymerase I. Chosen peptide has some conservation with corresponding protein from Populus but not Oryza sativa.
Because of the complexity of the retroviral life
cycle and the small number of viral proteins, important viral-
host relationships likely remain to be discovered. http://64.233.167.104/search?q=cache:T_gYO6DolZwJ:www.idm.pitt.edu/JCArticle_JAN23.pdf+nuclear+pore+protein+znrd1&hl=en&ct=clnk&cd=13&gl=us
HIV-1 exploits multiple host proteins during infection. We
performed a large-scale siRNA screen to identify host
factors required by HIV-1 and identified over 250 HIV-
dependency factors (HDFs). These proteins participate in
a broad array of cellular functions and implicate new
pathways in the viral lifecycle. Further analysis revealed
previously unknown roles for retrograde Golgi transport
proteins (Rab6 and Vps53) in viral entry, a karyopherin
(TNPO3) in viral integration, and the Mediator complex
(Med28) in viral transcription. Transcriptional analysis
revealed that HDF genes were enriched for high
expression in immune cells suggesting that viruses evolve
in host cells that optimally perform the functions required
for their lifecycle. This effort illustrates the power with
which RNA interference and forward genetics can be used
to expose the dependencies of human pathogens such as
HIV, and in so doing identify potential targets for
therapy.
i just found another great article out of china that they have discovered
ZNRD1) mediates multidrug resistance of leukemia cells -- to me this means ZNRD1 has a role in slowing or stopping a blood based disease leukemia just like it is the critical factor just discovered to be the slowing of hiv in the long term non progressors! where are these places??? Shen'yang, Liaoning, China Shaanxi, China. They sound like cool places but hard to pronounce.
Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2
Liu Hong1, Ying Piao2, Yu Han1, Jun Wang1, Xiaoyin Zhang1, Yulei Du1, Shanshan Cao1, Taidong Qiao1, Zhen Chen1 and Daiming Fan1 1 State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China and 2 Department of Oncology, The General Hospital of Shenyang Military Region, Shen'yang, Liaoning, China
Requests for reprints: Daiming Fan, State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China. Phone: 86-29-3373974; Fax: 86-29-2539041. E-mail: hlhyhj@hotmail.com
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Dysregulation of Apoptosis in Cancer -
JC Reed - Journal of Clinical Oncology, 1999 - jco.ascopubs.org
... a potent death-suppressing protein has been ... 2 family proteins and the pore-forming
domains ... membrane, endoplasmic reticulum, and nuclear envelope (reviewed in ...
http://jco.ascopubs.org/cgi/content/abstract/17/9/2941
i did a search and the very first time that ZNRD1 was discovered was in this paper in 1999
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watch the six hour video of the top vaccine researches meeting as i did
they are not stopping and they are increasing thier efforts
the link is above
a vaccine for treatment will come before a vaccine for prevention
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adjuvant
basically this is a huge huge topic but vaccines can be only made effective when there is some added chemical extra something or such like alum (used by men to stop bleeding in shaving it is injected with most vaccines) to trick the immune system into a major attack, and now they are finding that this extra something is extremely important and may determine if a vaccine works at all or not... AND that there is complex new immune responses involved with the cell distruction and cell death that this adjuvant causes and in chemo therapy they discovered that it doesnt kill the cancer but actually the chemo kills the cells and the cells dying is like a giant signal to immune system to kill the cancer (until these papers science though chemo was killing the cancer)
No no no. This all can be applied to hiv vaccines and immune system understanding. big big discovery
Explaining alum: immunologists' dirty little secret
http://www.stanford.edu/class/mi104/Class%202/Lecture%202%20Toll.doc
http://www.focosi.immunesig.org/adjuvants.html
http://www.vetscite.org/publish/articles/000027/index.html
http://www.iayork.com/MysteryRays/index.php?s=faist
The immunologist’s dirty little secret” is a secret no longer, and it’s not even so dirty any more now that we have started to understand a little about it. The “dirty little secret” line was coined by Charlie Janeway, in a 1989 essay1 that was one of the few really revolutionary single papers in immunology. As just about anyone even peripherally involved with immunology knows, Charlie was referring to the puzzle of how immune responses start. The principle of vaccination has been known for over 2000 years. The ancient Greeks were aware that individuals who recovered from the plague had immunity, or diminished susceptibility, when exposed for a second time to the disease. Remarkably (to me, anyway) they also show that one of the major reasons chemo- and radiotherapy works is exactly this — the therapy damages the tumor and induces it to release danger signals, especially HMGB1, that signal through TLR4; this TLR4-induced inflammation enhances the adaptive response to the tumor:12 Cancer patients and their physicians who receive and apply chemotherapy, respectively, do so in the genuine belief that the prime goal of therapy is to destroy tumor cells. Here, we show for the first time that anticancer chemotherapy has an additional, decisive effect. Dying tumor cells elicit an immune response that is required for the success of therapy. it kind of makes chemotherapy sound like cargo-cult medicine, or witch-doctory, trying to cause cell death even though that is only peripheral to the true therapeutic effect of priming adaptive immunity. Focusing on triggering cross-priming rather than cell death may offer new approaches to cancer therapy. The overall observation, of course, is further encouragement to the concept of cancer vaccines.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=162302
“Why,” he asked, “was the mere foreignness of a protein not enough to elicit immunity? Why did we need to add adjuvant (noxious substances like mineral oil, mycobacteria, or aluminum hydroxide) in order to get a decent response to a vaccine?” The self-nonself model neither predicted nor explained the need for adjuvant. Charlie gnawed at this problem (which he called the “immunologists’ dirty little secret”) for years, slowly coming to an important understanding that caused a major switch in immunological thinking. He decided that immune responses could not occur unless antigen-presenting cells were first activated, and that they were activated via pattern recognition receptors (PRRs) that recognized evolutionarily conserved molecules on infectious nonself organisms. In effect, he said that the immune system’s default state is off
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Altered Viruses Reversed Progressive Blindness, Studies Say
Washington Post - 1 hour ago
Three young adults barely able to see because of a congenital and progressive form of blindness have regained modest amounts of vision after getting genetically engineered viruses injected into their eyes, the leaders of two independent .
The company that is involved with this accournting to report is TARGETED GENETICS CORPORATION
from seattle
i went to thier website and was happy to find out they are working on HIV
i mean if they can do a little for blindness with genetic therapy maybe there is hope for thier techniques
in hiv therapy
every little step is good
http://www.targen.com/Pipeline_HIVAids%20Vaccine.htm
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ITK - new way to stop hiv directly
http://www.reuters.com/article/africaCrisis/idUSN28486470
also used a drug called BMS509744
Without the active protein, HIV cannot effectively take advantage of many signalling pathways within the immune system's T cells, which in turn slows or blocks the spread of the virus.
Henderson's group interfered with interleukin-2-inducible T cell kinase, or ITK, a protein that signals T cells to activate against disease-causing invaders like viruses.
http://www.reuters.com/article/africaCrisis/idUSN28486470
Schwartzberg said ITK also is being examined as a possible target for drugs to treat asthma or other ailments involving the immune response. A member of his team of scientists realized that the biological pathways the protein affected were the same ones that are important to the AIDS virus.
Working with human cells in a laboratory dish, the researchers used two different methods separately to inactivate ITK. One is a relatively new method called small interfering RNAs or siRNAs, which can stop certain genes from functioning.
They also used a drug called BMS509744, which already had been known to chemically interfere with the protein but had not been looked at in the context of fighting HIV infection.
Both methods succeeded in undercutting HIV infection."We didn't completely block (infection) but we certainly severely impaired it," Schwartzberg said. "It has minor effects at multiple stages of HIV life cycle, and together that all adds up to a more profound effect." Schwartzberg said it could be years before any drug based on the idea of inhibiting ITK could be tried in people Proceedings of the National Academy of Sciences, the scientists from the National Human Genome Research Institute (NHGRI) and Boston University managed to block HIV infection in the test tube.
They achieved this by inactivating a human protein expressed in key immune cells. Without the active protein, HIV cannot effectively take advantage of many signalling pathways within the immune system's T cells, which in turn slows or blocks the spread of the virus. Researcher Dr Pamela Schwartzberg said the team was "pleased and excited" by the outcome of the study.NHGRI scientific director Dr Eric Green added: "This new insight represents an important contribution to HIV research."Finding a cellular target that can be inhibited so as to block HIV validates a novel concept and is an exciting model for deriving potential new HIV therapies."
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http://www.reuters.com/article/africaCrisis/idUSN28486470
The result was a reduction of between 60% and 80% in luciferase activity, indicating a reduction in HIV transcription, Dr. Schwartzberg and colleagues found. On the other hand, increasing ITK expression, using a wild-type expression vector, increased luciferase activity by a factor of four. The researchers also tested whether blocking ITK could affect replication after cells were already infected, in this case with an HIV clone that expresses placental alkaline phosphatase on the surface of infected cells. Jurkat cells were infected for 24 hours before treatment with silencing RNA. After another 48 hours, cells in which ITK was silenced had a 68% reduction in intracellular p24 compared to control cells in which another protein was blocked. Blocking ITK also reduced the proportion of infected cells after 72 hours -- 6% versus 18% for control cells. "Inhibition of ITK either before or postinfection suppresses HIV replication," the researchers said. It's also important that -- unlike many of the cellular proteins in a T cell -- ITK does not appear to be critical for normal immune function. Mice engineered to lack the protein are capable of clearing any viral infections that have been tested, she said.
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IL2-inducible T-cell kinase, also known as ITK, is a human gene. from wikipedia
This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains SH2, SH3 and PH domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation.*** Pleckstrin is a protein found in platelets. The name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin homology domain (PH domain) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins. A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity. [***obviously this would be important in fighting off hiv T-cell proliferation and differentiation.]
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basically the scientists have discovered more and more detail about exactly how and what makes an elite controllers never get progression of disease from hiv and they think they can create med that can make everyone take advantage of what elite controllers have... a protein called FOXO3a in CM resilience ... cm is central memory t cell ... anyway they keep getting more and more great discoveries around why some people never get sick and it is turning out to be very clear and simple reasons and possibly able to mimic with new meds, probably ones that have few side effects and no resistance
http://www.amfar.org/cgi-bin/iowa/programs/resrch/record.html?record=61&tr=y&auid=3591881
In the Nature Medicine article, the authors show that one pathway responsible for this CM resilience involves the FOXO3a protein. The University of Montreal researchers drew blood samples and found that artificially silencing FOXO3a in test-tube experiments, using a range of gene therapy techniques, extended the life of CM cells from HIV-positive individuals on drug therapy to a length of time similar to that of CM cells from elite controllers. Defining exactly what is different about FOXO3a-related activity in the CM cells of elite controllers requires further study. But the work of Chomont, Routy, Haddad, and colleagues suggests that drugs capable of inhibiting FOXO3a might facilitate the maintenance or reconstitution of a more effective immune system in HIV-positive individuals. Dr. Haddad said in a March Toronto Globe and Mail article that these insights derived from HIV research could also have broad benefits for many other disorders, including cancers and other viruses.
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Best. Thread. Ever. Don't know why I'm just discovering it now. More more!
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ITK is looking more exciting every day i read it, they seem to already have ITK inhibitor drugs they are testing with asthma. in one science website in india called it "possible cure" !!!! see end of this post
http://www.nih.gov/news/health/apr2008/nhgri-28.htm
"ITK turns out to be a great target to examine," said Dr. Schwartzberg, noting that researchers had been concerned that blocking other human proteins involved in HIV replication might kill or otherwise impair the normal functions of T cells. According to Dr. Schwartzberg, ITK already is being investigated as a therapeutic target for asthma and other diseases that affect immune response. In people with asthma, ITK is required to activate T cells, triggering lung inflammation and production of excess mucus.
"There are several companies who have published research about ITK inhibitors as part of their target program," Schwartzberg said. "We hope that others will extend our findings and that ITK inhibitors will be pursued as HIV therapies." NHGRI researchers received support for this work from the NIH Intramural AIDS Targeted Antiviral Program. Chemical compounds used in the research were synthesized at the NIH Chemical Genomics Center, which was established through the NIH Roadmap for Medical Research and is administered by NHGRI.
Human protein: Possible answer to HIV cure
However, the researchers reveal that the ITK suppression did not interfere significantly with T cells’ normal ability to survive and the ITK deficient mice ...
www.igovernment.in
http://www.igovernment.in/site/human-protein-possible-answer-to-hiv-cure/
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Itk inhibitors
2-amino-5-[(thiomethyl)aryl]thiazoles as potent and selective Itk inhibitors.
2-amino-5- thiomethyl aryl thiazoles
http://www.ncbi.nlm.nih.gov/pubmed/16481166
2006 Aug these scientists discovered this molecule, drug, medicine against asthma immune mucous in lungs which now two years later other scientists found fights hiv potently, now they may have to tailor the molecule a bit to make it best against hiv, or less side effects etc... these people may one day be know as discovering the best treatment for hiv
Bioorg Med Chem Lett. 2006 Aug 1;16(15):4148. Doweyko, Arthur M [added].
Discovery and structure-activity relationships
of 2-amino-5-[(thiomethyl)aryl]thiazoles as potent and selective Itk inhibitors.
Das J, Liu C, Moquin RV, Lin J, Furch JA, Spergel SH, Doweyko AM, McIntyre KW, Shuster DJ, O'Day KD, Penhallow B, Hung CY, Kanner SB, Lin TA, Dodd JH, Barrish JC, Wityak J.
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.
http://www.google.com/search?q=%22ITK+inhibitor%22&hl=en&start=10&sa=N
"ITK inhibitor" --- only 16 articles found means it is very very new
http://lib.bioinfo.pl/auth:Kanner,SB many articles here about it
hundreds of different thiazole molecules exist and could be tested for anti hiv properties
http://www.synthonix.com/thiazoles.htm
aminothiazole
Some thiazole derivatives, belong to a class of cyclic sulfur organo products containing sulfur atom (S) and often oxygen (O), nitrogen (N), hydrogen (H), as well as other elements, can find application for making biological activitive agents such as antiviral, antibacterial, antifungal , antituberculous, antbody and antifungal agents.
http://chemicalland21.com/specialtychem/finechem/2-AMINOTHIAZOLE.htm
thiol flavouring Thiazole and its derivatives are also used as thiol flavouring substances.
many are already used as food additives
http://www.inchem.org/documents/jecfa/jecmono/v44jec09.htm
http://www3.interscience.wiley.com/journal/112696266/abstract
Discovery and SAR of 2-Amino-5-[(thiomethyl)aryl]thiazoles as Potent and Selective ItK Inhibitors.
Jagabandhu Das, Chunjian Liu, et al. et al.
Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA
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CANADA CANADA CANADA recruiting elite controllers to take part in the next study
Sékaly's team is recruiting elite controllers to take part in the next study. It can be reached at hiv_controllers@umontreal.ca
i spoke with Elias Haddad for 45 min 9 months ago
CHARLIE FIDELMAN, Montreal Gazette
Published: Monday, May 05
http://www.canada.com/montrealgazette/story.html?id=c4e75d52-213f-474b-94ed-62ee99aa39fe
Published in the advance online edition of the journal Nature Medicine, the researchers explain how a protein in some people's DNA shields against life-threatening immune illnesses.
Moreover, when injected into sick tissue, this key protein - once modified - was able to reverse cell death in defective HIV cells. The discovery means researchers might have a reliable target for an HIV vaccine, experts said. "We're also focusing on cancer, another problem for which you need memory T cells," said Elias Haddad, adjunct professor in microbiology and immunology at U de M and McGill University.
The study compared three groups: an HIV-negative sample, an HIV-positive group whose infection was under control with medication, and a third group (the elite controllers) whose HIV showed no symptoms.
"They were better than healthy," Haddad said of the elites.
The secret of the elite controllers lies in a key protein called FOX03a.
Sékaly's team is recruiting elite controllers to take part in the next study. It can be reached at hiv_controllers@umontreal.ca
CD8 pd-1 CD8 pd-1 CD8 pd-1 CD8 pd-1
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050100&ct=1
Antigen Load and Viral Sequence Diversification
Determine the Functional Profile of
HIV-1–Specific CD8þ T Cells
this chart is amazing because it actually shows the evolution or changes in the immune system t cells epitope monthly
and how the virus evades
http://www.plos.org/press/plme-05-05-altfeld.pdf
CD8+ T cells
have furthermore suggested that ‘‘polyfunctional’’
CD8 T cells with the ability to mediate up to five
different effector functions (CD107a, interleukin [IL]-2,
tumor necrosis factor [TNF]-a, interferon [IFN]-c, and
macrophage inflammatory protein [MIP]-1b) in response to
stimulation by antigen may form the basis of a more effective
CD8þ T cell response . Similarly, differences between
antigen-specific CD8þ T cells from HIV-1 progressors and
nonprogressors with respect to up-regulation of programmed
death-1 (PD-1, also called CD279) and downmodulation
of the IL-7 receptor in chronic viral infection
(CD127) have been demonstrated. While PD-1 has
been described as a marker for activation and susceptibility
to apoptosis and CD127 down-modulation as a marker
for a lack of transition into memory T cells , both markers
have been linked to the functional exhaustion of CD8þ T cells
Immune exhaustion in HIV infection
2 articles discussing immune exhaustion and its prevention in HIV infection from PLoS Medicine
It’s the virus, stupid: immune exhaustion in HIV infection
As HIV disease progresses in a person infected with the HIV virus, a group of cells in the immune system, the CD8+ T lymphocytes, become “exhausted,” losing many of their abilities to kill other cells infected by the virus. For many years scientists have debated whether this exhaustion of CD8+ T cells is the cause, or the consequence, of persistence of the HIV virus. In a study published this week in PLoS Medicine, Marcus Altfeld and colleagues studied the immune response over time amongst 18 individuals who had very recently become infected with HIV.
These researchers found that the presence of high amounts of HIV in the blood seemed to cause CD8+ T cell exhaustion; when antigen was reduced, either as a result of treatment with antiretroviral drugs, or evolution of viral epitopes to avoid recognition by CD8+ T cells, these epitope-specific CD8+ T cells recovered some of their original functions. These findings suggest that CD8+ T cell exhaustion is the consequence, rather than the cause, of persistent replication of HIV.
hypothesized that reduction in the functional avidity of the
interaction between CD8þ T cells with their respective
epitope resulting from amino acid substitutions will also
affect the expression of PD-1 on those cells, indicating weaker
activation of these epitope-specific CD8þ T cells
The longitudinal
studies in individuals identified during primary HIV-
1 infection presented here suggest that the functional profile
of an epitope-specific CD8þ T cell response is largely
determined by the duration and intensity of antigenic
exposure, and is therefore mainly a consequence of viremia.
progressive chronic HIV-1
infection [12,35,41–43]. Further support for this selective
impairment of antigen-specific T cell function in chronic
infection is provided by the observation here that the loss of
functionality was restricted to HIV-1–specific CD8þ T cells,
whereas no significant changes occurred in the functionality
of CD8þ T cell responses toward EBV, CMV, and influenza
antigens in the same participants
This observation demonstrating a direct
link between the sequence evolution of a targeted epitope
and the ‘‘functionality’’ of the ex vivo response furthermore
emphasizes the necessity for the concomitant evaluation of
autologous viral sequences in studies aimed at correlating
CD8þ T cell function, including PD-1 expression, with
markers of HIV-1 disease progression.
Overall, these data support a model in which antigenspecific
CD8þ T cell function in chronic HIV-1 infection, as
defined by the ability of epitope-specific CD8þ T cells to
activate multiple functional pathways ex vivo following
stimulation, is largely defined by the previous history of in
vivo antigenic stimulation. Similarly, these data support a
model in which continued recognition of specific antigen is
one of the major forces driving the functional impairment of
virus-specific CD8þ T cells during chronic persistent infections.
Importantly, this study underscores the relevance of
evaluating autologous viral sequences when interpreting data
on the functionality of virus-specific immune responses.
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long-acting anti-HIV skin patch
Future plans call for the development of a long-acting anti-HIV skin patch. The Company feels that this delivery method will result in markedly improved patient compliance.
---validate the Company's HivCide-I as a potential treatment for HIV/AIDS,
NanoViricides, Inc. (www.nanoviricides.com) is a development stage company that is creating special purpose nanomaterials for viral therapy
----anti-HIV drug candidates demonstrated significant therapeutic efficacy in the recently completed preliminary animal studies. The studies were performed at a Bio-Safety Level 3 Laboratory (BSL-3) facility in Boston, MA. These mouse model studies were conducted by Dr. Krishna Menon, PhD, VMD, MRCS, a world-renowned authority in preclinical and toxicological studies of innovative therapeutics.
Anti-HIV NanoViricide Drug Candidate Demonstrates Significant Therapeutic Efficacy in Animal Trials
WEST HAVEN, CT | Posted on May 5th, 2008
http://www.nanotech-now.com/news.cgi?story_id=29215
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Monoclonal Antibodies --
According to harvard,1/3 of all drugs in development for all diseases are Monoclonal Antibodies according to harvard biovisions, and these Monoclonal Antibodies have no side effects and no toxicity because they are immune proteins -- stable in blood -high specific for targets --no problems with toxicity- also they are immune proteins exactly like human-- several have been approve for therapies
"Monoclonal Antibodies perfect human molecules that were designed by nature for our defense is now being created by man in many forms to treat diseases." says harvard biovisions video. I went to the usa gov website for clinical trials and searched thru 3700 trials first for all Monoclonal Antibody Trials and then i had to go page by page to find just the Monoclonal Antibody trials that are being tried against HIV. It took 55 min. to pull this data from all the clinical trials at the .gov website here is the list of only... Monoclonal Antibody Trials against hiv.
TRIALS Monoclonal Antibody HIV http://clinicaltrials.gov/ct2/results?term=antibody&pg=2
Monoclonal Antibody
The Safety and Effectiveness of Human Monoclonal Antibody, F105, in the Treatment of HIV
Condition: HIV Infections
Intervention: Drug: F105 Monoclonal Antibody (Human)
http://clinicaltrials.gov/ct2/results?term=antibody&pg=2
The Effectiveness of Human Antibodies in Influencing an AIDS-Like Disease in Monkeys
Condition: HIV Infections
Interventions: Biological: gp160 MN/LAI-2; Biological: Aluminum hydroxide
Phase I/II, Open-Label Trial of Three Monoclonal Antibodies
Condition: HIV Infections
Intervention: Drug: Potent HAART during acute or early HIV-1 infection
Immunologic Memory (Supp. of ATN 024)
Conditions: Healthy Subjects; HIV Infections
Interventions: Biological: Engerix B; Biological: Twinrix for ATN 024; Biological: Recombivax; Biological: Twinrix for ATN 025
Safety and Efficacy of an Antibody to CCR5 in Individuals With HIV Who Are Not Currently on Antiretroviral Therapy
Condition: HIV Infections
Intervention: Drug: CCR5mAb004
An Escalating Dose Tolerance Trial of BG8962 (rCD4) in Patients Who Are HIV Antibody Positive
Condition: HIV Infections
Intervention: Drug: CD4 Antigens
Bavituximab Repeat-Dose Trial in Patients Co-Infected With Chronic Hepatitis C Virus and Human Immunodeficiency Virus
Conditions: Hepatitis C Virus; HIV Infections
Interventions: Drug: bavituximab; Drug: bavtuximab
Study of PRO 140 by Subcutaneous Administration in Adult Subjects With HIV -1 Infection
Conditions: HIV -1 Infection; HIV Infections
Interventions: Drug: PRO 140 (humanized monoclonal antibody to CCR5); Drug: Placebo Comparator
Hyperimmune IVIG in Slowing Progression of Disease in HIV-Infected Children
Condition: HIV Infections
Intervention: Drug: Anti-HIV Immune Serum Globulin (Human)
Plus a few trials i thought were interesting one for woman and hpv and other transfusing blood from a person who controls hiv into a person whose body does not
White Blood Cell Infusion to Treat HIV Infection
Condition: HIV Infections
Intervention: Drug: Cell Transfer Some HIV-infected individuals have a white blood cell marker known as HLA-B*57 that appears to help control the progress of the disease; however, not all who have the HLA-B*57 marker are able to control the infection. This study will examine the effects of giving white blood cells with HLA-B*57 from an individual who controls HIV infection to an individual who cannot control HIV infection, as a form of HIV treatment.
Treating Children With Severe Combined Immunodeficiency Disease
Anti-CD45 Monoclonal Antibody, Alemtuzumab, and Fludarabine Followed By Donor Stem Cell Transplant in Treating Children With Severe Combined Immunodeficiency Disease or Other Primary Immunodeficiency Disorder
Condition: Precancerous/Nonmalignant Condition
Interventions: Drug: alemtuzumab; Drug: anti-CD45 monoclonal antibody; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: chemotherapy; Procedure: monoclonal antibody therapy
Recruiting safety of and Immune Response to the Human Papillomavirus (HPV) Vaccine in HIV Infected Women
Conditions: HIV Infections; Sexually Transmitted Diseases
Intervention: Biological: Quadrivalent human papillomavirus vaccine
Cisplatin, Fluorouracil, Cetuximab, and Radiation Therapy in Treating Patients With HIV and Stage I, Stage II, or Stage III Anal Cancer
Condition: Anal Cancer
Interventions: Drug: cetuximab; Drug: cisplatin; Drug: fluorouracil; Procedure: chemotherapy; Procedure: monoclonal antibody therapy; Procedure: radiation therapy
Recruiting Human Papillomavirus Vaccine Therapy in Treating Men With HIV-1 Infection
Conditions: Infection; Precancerous/Nonmalignant Condition
Interventions: Drug: quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine; Procedure: recombinant viral vaccine therapy
on another related topic
Cloning of human genetic material and development of living biological production systems has allowed the production of virtually any recombinant DNA based biological substance. Since the expiry of the patent of the first approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more ) ‘copying’ and marketing of these biologics (thus called biosimilars) can be offered by any other biotech company. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches. Recombinant therapeutic proteins are of a complex nature ( composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells ( bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein. Biosimilars or Follow-on biologics are terms used to describe officially approved new versions of innovator biopharmaceutical products. Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity These proteins are made in living cells ( bacteria, yeast, animal or human cell lines). human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches. Recombinant therapeutic proteins are of a complex nature ( composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms. from wikipedia.com
multimedia.mcb.harvard.edu/
About Biovisions at Harvard University
The continuing quest for new and more powerful ways to communicate ideas in biology is the focus of BioVisions at Harvard University. ... multimedia.mcb.harvard.edu/biovisions.html cellular Visions: The Inner Life of a Cell
http://www.nature.com/nri/journal/v8/n6/full/nri2347.html
The investigators found that inducible T-cell kinase (ITK) was an important protein for HIV spread. The leader of the study, Pamela Schwartzberg, said: "Suppression of the ITK protein caused many of the pathways that HIV uses to be less active, thereby inhibiting or slowing HIV replication." (The Press Association, 28 April 2008.) Whereas ITK is normally involved in T-cell activation, "many of the pathways regulated by ITK were also needed for HIV to take hold in the body." (BBC News, 30 April 2008.) Importantly, preventing HIV spread through inhibition of ITK in mice did not cause significant immunosuppression as "mice deficient in ITK were still able to ward off various types of viral infection." (The Press Association, 28 April 2008.) However, some immune responses in asthma and allergy were impaired, in agreement with ongoing investigations of ITK inhibitors to treat these conditions in humans. Schwartzberg's team plans to "continue to investigate the biological mechanisms underpinning the ITK–HIV relationship," (US News, 13 May 2008) and it is hoped that companies currently exploring the potential of ITK inhibitors to treat allergic diseases will now expand their explorations to study the effects of these drugs on HIV.
http://huehueteotl.wordpress.com/2008/04/29/human-protein-may-offer-novel-target-for-blocking-hiv-infection-successful-in-lab/
This is very exciting because what it says is that there are ITK inhibitors already in test on humans for alllergies and ashma and that they should work to suppress the hiv virus also. so this would be a quick approved drug if it works because it is already far in the pipeline.
http://www.sciencedaily.com/releases/2008/05/080523162920.htm
TAK-779, which didn't include the harmful ammonium salt. After testing, they found that attaching 12 molecules of the modified drug (SDC-1721) to one nanoparticle of gold restored the drug's ability to prevent HIV infection in primary cultured patient cells. We've discovered a non-harmful way to improve the strength and efficacy of an important drug," Melander says. "There's no reason to think that this same process can't be used with similar effect on other existing drugs."
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Virionyx microparticle immune stimulator (MIS416)
This is big big news, as science learns how to actually make "SHAPES" that stimulate the immune system, this is a giant leap forward for many diseases. shapes means instead of the actual molecule from a bug they create a tiny shape that is similar but not the bug, for example, think of sweet and low vs. sugar, both have the shape that you taste as sweet but one has a big calorie attached and one is just a fake molecule...
Virionyx "mis416" microparticle immune stimulator (MIS416) PEHRG214
In a pandemic situation, it has the potential to protect workers at the front line and the public.
These scientists are working on "mis416" - a tiny micro-particle that's big news in medical circles.
It could be used to fight the flu, hepatitis and HIV and, while it is still a long way off, even some forms of cancer.
The micro particle technology is the therapy of the future. It doesn't use drugs but stimulates the body's own immune system to fight disease.
By ingesting the micro-particle, the patient powers up their own immune cells, which in turn attack incoming viruses.
“The idea of using a patient’s own immune system to prevent infection is very exciting. Agents like our micro particle I think hold the key to that,“ says Simon Wilkinson, Virionex CEO.
Like many medical innovations, "mis416" was discovered by accident.
“We started studying this secondary to military applications in the United States and we were determining its effect on treating anthrax,” says Dr Frank Gelder, Founding Scientist.
It resisted anthrax in animal studies, but did even better against the flu.
“The micro particle in preliminary studies has shown we can reduce the death rate to zero and the acute illness phase by 40 to 60 percent,’ says Dr Gelder.
But this is much more than just another flu treatment.
“This micro particle has the potential to replace toxic and expensive therapies for treating viral infections such as hepatitis,” Dr Gill Webster, Virionyx Chief Scientific Officer.
And with the Government just turfing more than a million dollars of expired antibiotics and Tamiflu pills, stockpiled in case of a bird flu pandemic, mis416 has obvious advantages.
Its very easy to manufacture in large quantities and it has a reasonable cost compared to a lot of pharmaceuticals, and the other key thing is it has a long shelf life.
Auckland biotech company Virionyx is due to test the micro-particle on humans within the next 12 months. And it will eventually be available as a nasal spray. By then, hopefully, mis416 will have a catchier name.
http://www.tv3.co.nz/News/HealthNews/NewflumedicinemayalsofightHIVandhepatitis/tabid/420/articleID/57889/cat/59/Default.aspx
http://www.google.com/search?hl=en&q=Virionyx&btnG=Google+Search
http://www.virionyx.com/internal.aspx?mode=43&mast=mast7.jpg
http://www.virionyx.com/
Anti-AIDS Polyclonal Immunotherapy:
PEHRG214 is a polyclonal antibody therapy that targets multiple epitopes on the Human Immunodeficiency Virus (HIV-1) that are not recognised by the human immune system, are highly conserved, and functionally important. PEHRG214 is targetted at HIV infected patients with AIDS and has successfully completed three Phase 1 safety trials. A US Phase 2 safety and efficacy trial is due to commence late 2006.
http://www.virionyx.com/internal.aspx?mode=25&mast=mast2.jpg
The broadest aspect of the company’s patent portfolio covers the identification of specific epitope regions of, for example HIV protein (or other viral proteins) which fail to elicit an immune response in humans, but which do elicit a response in non-human mammalian subjects.
Such “alternate immunological regions” are rapidly becoming the focus of international research efforts as they may provide the functionally relevant targets for therapeutic and preventative vaccine development. The patents already held by Virionyx however reserve any such vaccine candidate targets as proprietory to the company.
http://209.85.173.104/search?q=cache:fgYXP2CAW9AJ:bio08.nzbio.org.nz/resources/uploads/bio08-virionyx.pdf+mis416&hl=en&ct=clnk&cd=3&gl=us
COMPANY PROFILE
Virionyx is a public unlisted biopharmaceutical product development
company based in Auckland, New Zealand. The company specialises in the
development of immune based therapeutics using patented discoveries and
proprietary technologies.
The company’s lead drug candidate,
PE
HRG214, represents a new biological
approach to the treatment of HIV infected patients who have progressed to
AIDS. Currently in US based Phase 2 trials,
PE
HRG214 is a polyclonal caprine
(goat) IgG preparation containing antibodies that target highly conserved
regions on HIV not recognised by the human immune system.
Virionyx has also designed and manufactured a microparticle immune
stimulator (“MIS416”) with multiple pathogen-associated molecular pattern
recognition receptors (TLR & NOD ligands) that act in a safe, well defined and
synergistic manner. In the presence of immunogens, the microparticle also
amplifies both cellular and humoral adaptive immune responses and thus it is
an effective and potent immuno-adjuvant.
FOCUS FOR BIO 2008
Virionyx is looking to partner two programmes:
• Passive immunotherapeutic for HIV/AIDS which has mechanism
distinct from existing anti-virals
• Microparticle immune stimulator – a potent activator of both
innate and adaptive immune responses
KEY TECHNOLOGIES
• Lead Drug Candidate -
PE
HRG214 represents a new biological
approach to the treatment of HIV infected patients who have
progressed to AIDS
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ZNRD-1
ZNRD-1 is the new miracle discovery that could one day solve the entire crisis unless OPAL or VIRSYS therapy or many other new things etc does not do it first. Would it not be wonderful to have two or 3 miracle, and i hate to use that word, because it is not of god, but of science and of mens minds, but 3 choices in ways to completely stop the virus that are vaccine, or gene therapy or immune modulators and not toxic at all, i think we are close and ZNRD-1 could be one of them.
I have ZNRD-1 memorized since harvard discovered, 3 months ago, that all long term non progressors have this one changed gene in common this is a major revolution discovery, because it could have been 9 different genes and some non progressors has one some had mixes of the 9 and that could have meant hundreds of different types of LTNP and such but it turns out it is only one f$#king gene that separates me, and or everyone from a life without disease progression and a life with toxic meds, in other words all you need is to turn on or off this ONE gene this one gene and you are a LTNP. That is what harvard learned 3 months ago.
meds i am sadly about to start taking for the first time in my life, probably atripla, in the mean time i am going to research and read everything that has ever been written about ZNRD-1 and see if i can pull anything together and make some sense of this perhaps even new ideas ... there are over 119,000 entries in websites and news reports and pharma and bio tech websites and science papers found by a regular google search but there are only 165 if you search on science papers in medicine and pharma on this ZNRD-1. http://scholar.google.com/scholar?hl=en&q=znrd-1&um=1&ie=UTF-8&sa=N&tab=ws
There is already a drug that effects ZNRD-1 called Invitrogen.
Invitrogen is the Monoclonal Antibody H6 that causes ZNRD-1 to be expressed! Does that shut off hiv or does it turn hiv on? That is a question that i am sure harvard is working on now at least in monkeys and mice and soon in humans. Then they have to find a small molecule a drug that can have same shape and function as Invitrogen is the Monoclonal Antibody H6.
http://www.liebertonline.com/doi/abs/10.1089/153685904774129801
Duke in 2007 and harvard in 2008 both found ZNRD-1 was a big deal with hiv and progression but harvard found that it was the ONLY thing!!!! http://www.sciencemag.org/cgi/content/abstract/sci;317/5840/944
"One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)–B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents."
In 2005 china discovered that ZNRD-1 stops or slows cancer in stomach cancers and when I imagine and visualize that genes are expressed in different areas of body at different levels and that the intestine track is where hiv loves to replicate then this could be important. in other words, the stomach and the intestine have expression of certain genes and another system has other genes, so it is interesting that china discovered. Since stomach cells and intestine are part of same system and probably would have similar gene expression importance in both areas. ZNRD1 gene suppresses cell proliferation through cell cycle arrest in G1 phase.
http://www.ncbi.nlm.nih.gov/pubmed/15662122
here is the big harvard discovery on znrd-1
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/
Clostridium and hiv poz could this be why some have bad reactions to Clostridium difficile
http://www.springerlink.com/content/ccgcxmdbq5hffkf8/
oxford is in on this too...
Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells
http://carcin.oxfordjournals.org/cgi/reprint/bgm064v1
Well for those really adventurous poz guys who dont have many options, what was that movie where denzel washington saves his son at the ER .... i guess if 45 poz guys are dying every day in USA is not this a big enough emergency to try some of this stuff Anti-ZNRD1 on humans as compassionate use.... geezes it only costs three hundred bucks what are the compassionate use rules anyway.... i am sure the price will go up to ten million dollars per dose if they find out it works in humans
anyone up for trying a mouse Anti-ZNRD1 Polyclonal Antibody Catalog # H00030834-B01 Price $295
http://www.linscottsdirectory.com/datasheets/antibodies/znrd1-1
http://www.novusbio.com/data_sheet/index/H00030834-B01
Host: Mouse Immunogen: ZNRD1 (-, 1 a.a. ~ 126 a.a) full-length human protein.
Epitope:MSVMDLANTCSSFQSDLDFCSDCGSVLPLPGNVRDFEGKVVKTSVVFHQLGTAMPMTCTNCKFQEKEDS [if you were God you could read this LOL}
Species Reactivity: Human. Other species have not been tested. Uses:Antibody Reactive Against Immunizing Recombinant Protein or Transfected Lysate on ELISA and Western Blot. Other applications have not been tested.
http://www.novusbio.com/search/index&search=ZNRD1 http://www.exactantigen.com/gene/9/6/0/6/ZNRD1-antibody.html
Name Species Summary Application Summary Price Data Sheet Add To Cart
H30834-A01 Mouse Polyclonal anti-ZNRD1 $225.00
H30834-Q01 ZNRD1 Recombinant Protein ( $305.00
H30834-R01 zinc ribbon domain containing, 1 (ZNRD1), transcript variant b, mRNA. $285.00
H30834-R02 zinc ribbon domain containing, 1 (ZNRD1), transcript variant a, mRNA. $285.00
H30834-M01 Mouse Monoclonal anti-ZNRD1 (6C12) $295.00
H30834-B01 Mouse Polyclonal anti-ZNRD1 - zinc ribbon domain containing, 1, MaxPab Antibody $295.00
H30834-T01 zinc ribbon domain containing, 1 293T Cell Transient Overexpression Lysate (Denatured) $250.00
considering all the terrible things everyone seems to put in thier bodies, sugar, alcohol, cigarette smoke, crack, meth, etc, can someone please explain why we can try a mouse Mouse Monoclonal anti-ZNRD1 antibody??? What would it do anyway?
If the 45 people with aids who die every day in usa had the chance, say, well hello sir, we just found out that all people who are LTNPs and do not progress to aids have this special gene ZNRD1, and hey we have the mouse anti-ZNRD1 and we thought you may only have a week or a month or two to live and hey we are going to just leave this sample in the room and if you want to try it then it is at your own risk ... i mean considering how many hiv pos homeless guys are killing themselves with meth, why
why do we have to wait for the mice and the monkeys tests and such.what is the compassionate use policy and who has control of what people put in thier bodies and why can govt allow basically tacitly allow meth use, because of open borders and no safety net for poor, and the economic demolishon derby that is our modern economy. winner takes all
why do people use meth when they are poz, i say half the reason is the virus is in the brain and it causes bad decisions to be made, and hey, ask anyone who has lived how a small little bad decisions can make a mess out of life, anyway,
here is a cool link to find all the cool things this znrd-1 does in body
http://www.ihop-net.org/UniPub/iHOP/gs/98938.html
mediates multidrug resistance of gastric cancer through regulation of P-gp and ZNRD1
i guess we should be happy that it at least exists so they can try in in experiments
http://www.biocompare.com/matrixsc/3194/2/6/51272/ZNRD1.html
even wikipedia has info on it
http://en.wikipedia.org/wiki/ZNRD1
(2004). "Suppression of the cell proliferation in stomach cancer cells by the ZNRD1 gene.".
(2005). "ZNRD1 gene suppresses cell proliferation through cell cycle arrest in G1 phase.". ------this alone seems to me like it could stop hiv deal in its tracks but who knows, science will find out soon.
(2007). "Mechanisms of growth arrest by zinc ribbon domain-containing 1 in gastric cancer cells.". Carcinogenesis 2
other subjects
selection of optimal immunization schedules for T cell-based vaccines.
CD8 and PD-1 http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/
Tracking CD8 T Cell Responses to Successful Vaccines
In the new issue of Immunity, Rafi Ahmed and colleagues from Emory University's Vaccine Center offer a detailed analysis of both the acute and memory CD8 T cell responses to two highly efficacious vaccines: yellow fever (YFV) and Dryvax (smallpox vaccine). Both vaccines induced vigorous CD8 T cell activation that peaked around two weeks after administration. Activated CD8 T cells (assessed by a combination of markers include CD38, HLA-DR, Ki-67 and Bcl-2) represented 12-40% of peripheral blood CD8 T cells at this timepoint. The authors estimate that each virus-specific naïve CD8 T cell responding to the vaccines likely divided 16-20 times, a finding that echoes estimates from murine studies (which have suggested each responsive naïve CD8 T cells undergoes around 15 divisions). This represents a 10,000-100,000-fold expansion of each virus-specific CD8 T cell. In both cases, these T cells express high levels of the activation marker CD38. One of the ongoing mysteries of HIV pathogenesis is the presence of elevated levels of CD38-expressing CD8 and CD4 T cells, the specificity of which has remained elusive for over two decades now. One possibility raised by these studies is that these activated T cells in HIV infection are in fact virus-specific, but represent newly generated HIV-specific naive T cells that are activated by HIV antigens in overlapping waves after exiting the thymus. While the daily output of HIV-specific naive T cells would be expected to be low in chronic infection, recent studies have shown rare naive T cells can expand prodigiously upon activation. inally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8+ T cells specific for persistent viruses. These results provide a benchmark for CD8+ T cell responses induced by two of the most effective vaccines ever developed. he researchers calculated that these responses would persist at substantial levels for at least 20 years; a separate analysis showing detectable memory CD8 T cell responses to Dryvax in individuals who received the vaccine ~50 years ago is cited in support of this extrapolation.
Los Alamos HIV sequence database ????do germ warfare and nuclear bombs ????
Does anyone else find it bad and strange and wrong and such that Los Alamos national labs which is like suppose to do germ warfare and nuclear bombs has the Los Alamos HIV sequence database, damn obviously they are keeping all the varients in case they want to use it in some terrible way, why cant all the money that goes into war and killing people go toward medical care in this country... http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/
a mutation in the tat gene that is present in less than 1% of the clade B isolates in the Los Alamos HIV sequence database.
First Human Anti-PD1 Antibody Trial Results Published
To the best of my knowledge, these are the first data to be published on the use of the anti-PD1 approach in humans. The goal is to revive exhausted and dysfunctional T cell responses, in this case against cancer. This was a Phase I, single dose (in most cases) study involving people with a variety of very advanced cancers, and I'm not knowledgeable enough about these conditions to be able to evaluate the authors claims regarding clinical benefit. It will also require much more work to establish the safety and tolerability of the approach in other settings. Anti-PD1 antibodies are being studied in animal models as potential immunotherapies for both HIV and HCV. Clinical Cancer Research 14, 3044-3051, May 15, 2008.
doi: 10.1158/1078-0432.CCR-07-4079 Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies
Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells
http://carcin.oxfordjournals.org/cgi/reprint/bgm064v1
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Symphogen - major breakthrus teaming with genetech the top gene science corp working on amazing Anti-HIV Antibodies /// symphogen against pathogenic viruses, including HIV/// Symphogen developed the concept of a polyclonal Master....by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies
Symphogen, a Dutch or danish company, (you gotta love the dutch they are liberal, tall, blond, and just passed a law making it legal to have sex in all public parks in amsterdam) anyway they are working on amazing Anti-HIV Antibodies. oops this may be danish company, but they are cute too...
Jun 10 2008, 12:56 PM EST
Symphogen and Genentech Partner on Infectious Disease Antibody Drugs
http://www.genengnews.com/news/bnitem.aspx?name=36965264&source=genwire
GEN News Highlights Symphogen could earn over $300 million through a discovery and development deal with Genentech. Symphogen will use its Symplex antibody-discovery platform to identify compounds against three infectious disease targets.
Under the global strategic collaboration, Genentech will make an upfront payment as well as an equity investment. The firm will also fund R&D activities. Additionally, Symphogen is eligible to receive milestone fees upon the success of certain research and development goals.Genentech will obtain an exclusive, worldwide license to compounds developed through this agreement. If a drug is commercialized, Symphogen will earn royalties.Genentech will also gain access to Symphogen’s Sympress™ technology to produce recombinant polyclonal antibodies. It uses a mammalian-expression platform to enable the manufacturing of target-specific, fully human recombinant polyclonal antibodies.The Symplex process begins by isolating B lymphocytes from naturally immune human donors displaying a high number of antibodies against a particular target antigen. It enables the exact identity of the original donor antibody repertoire to be maintained and mimics the natural human immune response, according to Symphogen. Sym002 Sym002 is composed of recombinant polyclonal anti-vaccinia virus antibodies to replace existing anti-vaccinia hyperimmune immunoglobulins (VIG).Development of rpAb
RpAb: The Next generation of Antibody Therapeutics? RpAb: A New Class of Therapeutic Antibodies
Silobreaker: Test Detects Anti-HIV-1 and Anti-HIV-2 Antibodies
The new Vitros Anti-HIV 1+2 assays can be run in a fully automated, random access format ... Danish biopharmaceutical company Symphogen A/S signs strategic ...
www.silobreaker.com/DocumentReader.aspx?Item=5_867999756
2006;12(16):2007-15. Recombinant human polyclonal antibodies: A new class of therapeutic antibodies against viral infections. Bregenholt S, Jensen A, Lantto J, Hyldig S, Haurum JS. Symphogen A/S, Lyngby, Denmark.
The mammalian immune system eliminates pathogens by generating a specific antibody response. Polyclonality is a key feature of this immune response: the immune system produces antibodies which bind to different structures on a given pathogen thereby increasing the likelihood of its elimination. The vast majority of current recombinant antibody drugs rely on monospecific monoclonal antibodies. Inherently, such antibodies do not represent the benefits of polyclonality utilized by a natural immune system and this has impeded the identification of efficacious antibody drugs against infectious agents, including viruses. The development of novel technologies has allowed the identification and manufacturing of antigen-specific recombinant polyclonal human antibodies, so-called symphobodies. This review describes the rationale for designing drugs based on symphobodies against pathogenic viruses, including HIV, vaccinia and smallpox virus, and respiratory syncytial virus.
Genentech: collaboration prompts speculation over infectious ...
Having entered into a strategic collaboration with Symphogen, Genentech is set ... suggest that Genentech might even be looking to move into the HIV arena. ...
www.pharmaceutical-business-review.com/article_feature.asp?guid=50996BD0-5DEF-478A-B270-AD25E0D719BC
CellTherapyNews — Cell Therapy News Home
HIV Therapy Greatly Extends Life of Key T Cells, Scientists Find Interleukin-2 (IL-2), ... The license agreement allows Symphogen to use PER. ...
www.celltherapynews.com/index.cfm?act=nl&do=newsletter&nl_ID=101
Bregenholt,S Symphogen has developed technologies to capture the advantages of antibody ... including HIV, vaccinia and smallpox virus, and respiratory syncytial virus. ...
lib.bioinfo.pl/auth:Bregenholt,S
Expert Opinion - Expert Opinion on Biological Therapy - 6(9):905 ...
To achieve this, Symphogen developed the concept of a polyclonal Master ..... by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 ...
www.expertopin.com/doi/abs/10.1517/14712598.6.9.905
http://www.pharmaceutical-business-review.com/article_feature.asp?guid=50996BD0-5DEF-478A-B270-AD25E0D719BC
Gilead’s Atripla, Lower Costs
Provide Lift To First Quarter
By Randall Osborne
West Coast Editor
Gilead Sciences Inc.’s HIV steamroller charged on,
helped by strong sales of Atripla in the first quarter (though
Truvada and Viread dipped) plus lowered expenses, and the
firm bolstered its position in antibiotics with Phase III data
on inhaled aztreonam lysine for cystic fibrosis patients with
pulmonary Pseudomonas aeruginosa.
“Ultimately, I’m sure somebody will [challenge Gilead
in HIV], but in terms of first-line therapy, Atripla’s looking
pretty unassailable,” said Sharon Seiler, analyst with Punk,
Ziegel & Co. in New York.
Earnings were disclosed Thursday, followed the next
day by detailed results from the aztreonam study. Gilead’s
stock (NASDAQ:GILD) closed Friday at $82.39,http://209.85.215.104/search?q=cache:mMSaCdTD_ogJ:www.symphogen.com/c/document_library/get_file%3FfolderId%3D30%26name%3DDLFE-177.pdf+Symphogen+hiv&hl=en&ct=clnk&cd=4&gl=us
In the summer of 2000, Symphogen was founded in Copen-
hagen, Denmark, to discover and manufacture polyclonal and
MAbs aimed at infectious diseases and cancer. Those diseases
present very complex targets – rapidly evolving organisms and
cells changing their appearance and structures to hide from
monoclonal antibodies and targeted therapies.
That rapid evolution is why we need new flu vaccines on
a regular basis, why cancers escape from previously effective
chemo and how HIV keeps coming back after each new drug
therapy. Symphogen’s team believes that striking at multiple
targets simultaneously will make it tougher for them to
escape and mutate. Big Discovery Advantage
Antibody molecules have a very complex genetic origin,
with millions of possible gene combinations going into the
final output. How can Symphogen come up with a finite num-
ber of antibodies that are likely to have therapeutic value?
By letting natural immune evolution figure out the
important antibodies to get the job done.
The Symplex platform technology uses naturally occurring
antibody-producing B cells from naturally immune humans as
the source of antibody genes. (This is starting to sound like an
organic diary.) Unlike many of the competing antibody compa-
nies, Symphogen’s approach does not require use of other
folks’ patented technologies, like hybridoma, phage display or
directed evolution. Saves big bucks on royalties down the road.
Symphogen’s polyclonal approach means that its prod-
ucts are made by several cell lines at the same time, and in
controlled proportions. Otherwise, every batch would be
different, making regulatory agencies cranky. One of the
biggest challenges was getting all the different cell lines,
each producing its own antibody molecule, to divide at
similar rates. Faster growing lines wanted to take over the
combined fermentation vat, which would throw off the
proportions of the various antibodies
http://209.85.215.104/search?q=cache:mMSaCdTD_ogJ:www.symphogen.com/c/document_library/get_file%3FfolderId%3D30%26name%3DDLFE-177.pdf+Symphogen+hiv&hl=en&ct=clnk&cd=4&gl=us
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NEW SCIENTIFIC MEASURE OF HOW powerful each hiv med is in haart called IIP
1 = 90 percent
10 = 99.99999999 percent (eight 9s after the decimal point), meaning near total suppression
I could not find the list of drugs and thier 1 to 10 rating, anyone who can dig deeper please try and post...
The IIP calculation is scaled from less than 1 to 10 or greater, corresponding to logarithmic multiples of 10, where a 1 indicates a moderate level of drug suppression, at 90 percent, and 10 translates to 99.99999999 percent (eight 9s after the decimal point), meaning near total suppression.
Study results showed IIP ranges from around 1 to 4 for seven commonly used nucleoside reverse transcriptase inhibitors (NRTIs) and five integrase inhibitors (IIs); between 2 and 6 for five non-nucleoside reverse transcriptase inhibitors (NNRTIs) and for two fusion inhibitors (FIs); and between 2 and 10 for eight protease inhibitors (PIs) studied.
The Hopkins team says the IIP index will also guide future drug and vaccine development because it can be used to calculate which agents have the best potential for depressing levels of HIV in the body.
Moreover, says lead study investigator Lin Shen, M.D., a doctoral candidate in pharmacology at Johns Hopkins, the IIP could be measured for drugs slated for development, labeling them early on as potential failures if the values are too low.
Shen points out that drugs with lower indices, close to 1, such as the nucleoside reverse transcriptase inhibitor AZT (at 1.23), are known to work when matched with more powerful drugs, such as the non-nucleoside reverse transcriptase inhibitor efavirenz, at 5.72. http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20080611.083806&time=10%2000%20PDT&year=2008&public=0
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this is a bit of the answer to why some meds work in animals and not as well in humans, why meds work in first place and how proteins gene and cells all interact. amazingly in 2000 the drug companies thought the human genome was enough to solve all disease problems.. also some other great new papers and links below...
The body contains 25,000 genes, which can form as many as 1 million proteins interacting in hundreds of millions of ways. Perhaps only 5% to 10% of all protein and gene interactions have been documented so far. Network biologists' ultimate aim, still a decade away, is to create computer programs that could simulate the effects of drugs on cells
http://members.forbes.com/forbes/2007/0312/072.html in 2000, the best year ever for biotech venture capital, ...
Triumphant drug researchers assumed they had everything they needed. The human genome had just been mapped, and they had the supercomputers and tools to figure out which genes caused diseases. Who needs to bother with understanding how one gene interacts with thousands of others, let alone parsing the relationships among the hundreds of thousands of proteins these genes produce? The body-as-network is becoming a dominant metaphor for future drug research.
http://64.233.167.104/search?q=cache:iJMPBxWW6dcJ:helix-web.stanford.edu/psb06/bandyopadhyay.pdf+Ideker+hiv&hl=en&ct=clnk&cd=4&gl=us
DISCUSSION
In this report, we have identified a number of genes and pathways involved in
HIV latency and reactivation. This identification utilizes an integrated, literature
curated network of protein-protein interactions combined with time series
expression data for viral reactivation. There are several advantages to an
integrated network-based approach. First, the analysis suggests the involvement
of genes which are not differentially expressed or may even not have been
profiled under a given condition. It may be the case that these genes are post-
transcriptionally regulated which cannot be detected by the current approachGO Categories significantly enriched in the active networks for latent and early
reactivation stages of the HIV lytic cycle. The latent stage shows enrichment for apoptotic regulators
and the early stage shows enrichment for genes involved in control of transcription.
Even the simplest biochemical pathway - ligand, receptor, intracellular messenger, output - is far more complex than a simple back-of-the-envelope sketch. Signaling molecules have multiple kinase and phosphatase regulators, and gene promoters can be simultaneously influenced by both positive and negative transcription factors. Ligands, of course, are themselves subject to myriad control systems. http://www.the-scientist.com/2007/3/1/68/1/ Ideker joined the Whitehead Institute's coveted fellow program. There, he worked with Hood and others to introduce Cytoscape, an open-source software platform that allows scientists to create conceptual networks from databases of protein-protein, protein-DNA, and genetic interactions. 2 http://www.the-scientist.com/article/home/24477/
Biologists have long known that diseases such as cancer and diabetes are caused by a network of faulty proteins gradually going awry. But the complexity of these networks is beyond what anyone had expected. A recent analysis found 122 mutated genes involved in breast cancer and 69 in colon cancer. Scientists had estimated far fewer.
Notre Dame physicist Albert-László Barabási and others have shown that molecular networks inside our bodies share some basic similarities with the Internet. Typical proteins make relatively few links to other proteins, just as most Web sites link to only a few others. But a small handful of "hub" proteins are like the Google (nasdaq: GOOG - news - people ) of the protein world, connected to dozens of other proteins. "Disease is a breakdown of the network," he says. http://members.forbes.com/forbes/2007/0312/072.html "Can you imagine trying to predict how a computer chip is going to work when you are missing 90% of the circuitry? Yet that is exactly what the pharmaceutical industry does when it tries to make drugs," says Colin Hill, a physicist who heads Gene Network Sciences in Cambridge, Mass.
Theories about protein networks have been overlooked for decades, maybe because the idea is so obvious. Every gradeschooler knows the hip bone connects to the thigh bone. t is only within the past ten years that a new array of high-speed genetic tools has made network maps possible, by allowing researchers to look at thousands of genes or proteins at once and measuring how they interact. Then researchers can go back to cells or animals to test whether the predictions hold true. Concrete results are sparse, and systems biologists worry there is too much hype. "Anybody that thought the genome was going to directly provide drugs was a fool," says Leroy Hood. "Biological networks are not simple, and making drugs to affect them won't be simple. Drug companies don't really understand how far away we are." A few substantive ideas have emerged. Entelos, of Foster City, Calif., is helping drug companies simulate clinical trials for diabetes, asthma and other diseases using virtual patients that exist only inside computers. A two-year trial can be run in a few hours. Johnson & Johnson (nyse: JNJ - news - people ) says the Entelos program correctly predicted that a new class of diabetes drugs it was testing in mice would be ineffective in humans. "That sort of thing makes you start to be a believer," says Michael Jackson, who heads J&J's West Coast research labs
http://www.technologyreview.com/read_article.aspx?id=16468
Biomedical research these days seems to be all about the "omes": genomes, proteomes, metabolomes. Beyond all these lies the mother of all omes -- or maybe just the ome du jour: the interactome. Every cell hosts a vast array of interactions among genes, RNA, metabolites, and proteins. The impossibly complex map of all these interactions is, in the language of systems biology, the interactome. ...."For a while, we struggled to figure out what was going wrong with our analysis," says Ideker. After rechecking their data, Ideker and his team concluded that Plasmodium probably just had a somewhat different interactome. For pharmaceutical makers, the discovery of unique biological pathways, such as those found in the malaria parasite, suggests new drug targets. Theoretically, a drug that can interrupt such a pathway will have limited, if any, impact on circuits in human cells, reducing the likelihood of toxic side effects. Theoretically. In reality, pharmaceutical companies aren't exactly tripping over themselves to make new drugs for malaria -- a disease that strikes mainly in poor countries. But the general idea has great promise, says Ideker, who now plans to compare the interactomes of different HIV strains to see whether any chinks in that virus's armor come to light.
how the body heals dna damage
http://www.jacobsschool.ucsd.edu/news_events/releases/release.sfe?id=541
“It’s almost as if cells have something akin to a computer program that becomes activated by DNA damage, and that program enables the cells to respond very quickly,” said Mak. “And this program is easily recognizable as operating in everything from yeasts to humans and mice to fruit flies.”
http://www.medicalnewstoday.com/articles/23966.php
Ideker believes that the eventual wiring diagram of human cells will be similar to that of yeast; however a newly developed technology is needed to verify his theory. "You can't probe human cells as easily as we can yeast, but RNAi [RNA interference] lets you target pairs or triplets of genes," said Ideker. "This approach in humans, patterned on yeast experiments, could eventually lead to more sophisticated drugs and gene therapies based on taking down not single genes, but combinations of genes that cause disease."
in some ways, computational biology is more applicable to proteomics--the study of protein function in biological systems--where experts say the biomedical benefits of genomic knowledge will ultimately be found. "The actual network of molecular interactions is elucidated with proteomics," says Ideker. "Researchers in this field are asking two key questions: what are the proteinprotein interactions, and what are the proteinDNA interactions? These are the fundamental iterations that we're concerned with."
http://www.ehponline.org/realfiles/txg/members/2003/111-6/focus.html
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Boston (ChattahBox) - A new report has shown that people who are infected with HIV are living longer than ever, as the overall mortality rates for people with HIV continue to decline.
The new study was published in the July 2 issue of the Journal of the American Medication Association, and compared the mortality rate of people infected with HIV to the general population.
The study followed more than 16,000 people from different countries for over 6 years.
What they found over the course of the study is that now, people who are infected with HIV have the same risk of death after their first 5-years of being diagnosed as the general population.
There is no increased risk of death for someone infected with HIV until after they have the disease for over a 5-year period.
This is the first ever study to compare the death rate associated with HIV, to that of the general population.
The study has revealed that people are living with HIV longer than ever.
http://chattahbox.com/health/2008/07/02/people-infected-with-hiv-are-living-longer-than-ever/
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http://news.bbc.co.uk/2/hi/science/nature/7490384.stm
moral corruption of medical industry- BBC intellectual basis for activivism
make clear any disadvantages of the medicine, or, in fact, the fact that most people don't need this particular medicine - I would cite, for example, anti-depressants which are hugely oversold, especially in America. This is the sort of thing I mean by corruption. It's not legal corruption; it's moral corruption."
According to Sir John, the world is at a crisis point in terms of getting medicines to sick people, particularly in the developing world.
He says that the world needs an international biomedical treaty to iron out issues over patents and intellectual property.
also----------------
http://www.nakedcapitalism.com/2008/07/hoisted-from-comments-has-neo.html
theft of public goods through privatizations [worldwide -- this includes ALL hospitals in USA that were once public now private]
market fundamentalisms include financial opening and deregulation which, in different forms, were applied on a world scale right along with the theft of public goods through privatizations, et cet -- a 'grand' global looting had been unleashed in a (partially directed) effort to overcome systemic crisis.
3. In combination, the above two have generated greater class, ethnic, international and subnational tensions. The social relations of the world capital system have become quite strained, which is not to say that capitalism is 'doomed' but that its present form has become increasingly untenable and a 'change in state' is almost certainly unavoidable, in fact seems to be underway.
new york times
http://www.nakedcapitalism.com/2008/07/quelle-surprise-credit-card-companies.html
Credit card companies, having had Washington in the palm of its hand, is now facing a backlash as "gotcha" fees combined with a lot of Americans paying credit card rates that a generation ago would have landed the lender in jail (no joke, on an NPR show that I participated in, a caller said his uncle, a former loan shark, was in wonder of the credit card industry's practices. Said uncle did 15 years of hard time for lending at 17%).
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TRIM5alpha discovery -- someday TRIM5alpha could be a target for a new med or gene therapy hopefully
Abstract
The host factor alpha isoform of the tripartite motif 5 (TRIM5alpha) restricts human immunodeficiency virus type 1 (HIV-1) infection in certain non-human primate species. Restriction of HIV-1 is enhanced by binding of the viral capsid to cyclophilin A (CypA) in target cells, although CypA is not absolutely required for restriction in rhesus macaque cells. Simian immunodeficiency virus (SIV) is not restricted by rhesus macaque TRIM5alpha and its capsid does not bind to CypA. Here, the effect of lentiviral CypA dependence on restriction in different tissues was examined by engineering an HIV-1 capsid quadruple mutant (V86P/H87Q/I91V/M96I) lentiviral vector (HIVquad) that is CypA-independent. Whereas HIV-1 was restricted in rhesus macaque and owl monkey epithelial cells, infection with the HIVquad vector was efficient at high viral concentrations. In contrast, HIVquad was largely restricted in primary rhesus macaque CD34+ cells. Human epithelial and primary CD34+ cells were permissive for HIV-1, HIVquad and SIV, whereas transduction of human T cells by HIVquad or SIV was impaired. The restrictive human cells did not express increased levels of TRIM5alpha, and restriction was not relieved by abolishing CypA, consistent with HIVquad and SIV being CypA-independent. Pseudotyping of lentiviral vectors with the gibbon ape leukemia virus envelope altered their sensitivity to perturbations of the virus–CypA interaction compared to pseudotyping with vesicular stomatitis virus glycoproteins, suggesting that the viral entry pathway modulates restriction. Together, these studies reveal that an HIV-1 capsid quadruple mutant can partially overcome lentiviral restriction in non-human primate epithelial cells, but not in hematopoietic cells. Similarly, human cells vary in their permissiveness for CypA-independent lentiviruses, and suggest the presence of tissue-specific factor(s) that can inhibit lentiviral transduction independently of viral interaction with TRIM5alpha and CypA.
Keywords:HIV-1, restriction factors, TRIM5alpha, cyclophilin A, non-human primates, CD34+ hematopoietic cells
Main navigation http://www.nature.com/gt/journal/v15/n15/abs/gt200850a.html
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“There are several companies who have published research about ITK inhibitors as part of their target program,” Schwartzberg said. “We hope that others will extend our findings and that ITK inhibitors will be pursued as HIV therapies.”
with graphs
http://huehueteotl.wordpress.com/2008/04/29/human-protein-may-offer-novel-target-for-blocking-hiv-infection-successful-in-lab/
http://www.google.com/search?q=%22ITK+inhibitors%22
Selective Itk Inhibitors Block T-Cell Activation and Murine Lung Inflammation
Tai-An Lin,* Kim W. McIntyre, Jagabandhu Das, Chunjian Liu, Kathleen D. O'Day, Becky Penhallow, Chen-Yi Hung, Gena S. Whitney, David J. Shuster, XiaoXia Yang, Robert Townsend, Jennifer Postelnek, Steven H. Spergel, James Lin, Robert V. Moquin, Joseph A. Furch, Amrita V. Kamath, Hongjian Zhang, Punit H. Marathe, Juan J. Perez-Villar, Arthur Doweyko, Loran Killar, John H. Dodd, Joel C. Barrish, John Wityak, and Steven B. Kanner
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543
Received March 24, 2004
Revised Manuscript Received May 28, 2004
Abstract:
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive agents have not been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744, that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced functions including PLC1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. The inhibitors suppress the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma. Our findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases. http://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2004/43/i34/abs/bi049428r.html
Study Finds Potential New Therapeutic Target against HIV Infection
May 12, 2008
In a study supported by the National Institutes of Health (NIH), researchers have identified a potential new route for blocking the replication of human immunodeficiency virus by inactivating a human protein, interleukin-2-inducible T cell kinase (ITK), expressed in T cells of the immune system. The research article published in the recent online edition of the journal Proceedings of the National Academy of Sciences raises the possibility of developing new therapeutic strategies against HIV infection.
Currently, most of the drugs used to treat HIV are targeted against the proteins of the virus; however, the virus can genetically mutate at a high rate, leading to a change in viral proteins with the subsequent emergence of drug-resistant strains. The present study focuses on targeting the human cell proteins (ITK, a Tec family tyrosine kinase), as they are less susceptible to mutations in comparison with viral proteins. ITK, a signaling protein, helps in the regulation of T cell receptor (TCR)-induced activation of Ca (2+) mobilization, chemokine receptors and phospholipase C gamma-1. As the infection of T cells with HIV requires the activation of chemokine receptors with actin reorganization, ITK was targeted to examine its effect on the replication of the virus.
Pamela Schwartzberg, a senior investigator at the National Human Genome Research Institute, Bethesda, Maryland, along with coworkers, investigated the effect of ITK on HIV infection by using a ITK-specific small interfering RNA, a kinase-inactive ITK mutant or an ITK inhibitor. The study demonstrated that the inactivation of ITK caused a decrease in intracellular p24 levels, after the HIV infection, in addition to a reduction in the spread of virus within the culture. It was also noted that the entry of HIV virus was partially blocked but the expression of CD4 or CXCR4 (HIV coreceptors) and was not altered with ITK inhibition. Researchers found that ITK overexpression resulted in enhanced viral transcription and formation of virus-like particles, thereby suggesting that ITK inhibition could block HIV infection as it affects multiple steps in viral replication.
Previously, a study by François and Klotman (Journal of Virology, 2003) examined the relationship between phosphatidylinositol 3-kinase (PI3-kinase) pathway and HIV infection. The study demonstrated that the infection of CD4+ T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses, was inhibited by LY294002 (inhibitor of PI3-kinase), before gene expression and post virus entry. This inhibition was at concentrations which could not cause cell toxicity or a downregulation of the expression of HIV-1 coreceptor. Scientists concluded that the suppression of the viral infection (after virus entry and reverse transcription) was possible by inhibiting the PI3-kinase signaling pathway, thus proposing the use of this approach (of targeting cellular signaling pathways) to develop therapeutics for HIV infection.
According to the World Health Organization (WHO), around 33 million people are estimated to be infected with HIV, and more than 25 million have died since 1981, globally. As of November 2007, 30 antiretroviral drugs have been approved by the US Food and Drug Administration, which help in suppressing the human immunodeficiency virus but cannot totally eliminate them from the body. Currently, a lot of studies are being conducted to develop drugs that interfere with the lifecycle of the virus at different stages, like modulators of cellular metabolism that alter the cellular processes for HIV replication, insertion of modified genes to suppress the replication, and early inhibitors that prevent the entry of the virus into cells. The suppressors of ITK are also being examined as a therapeutic target for treating immune system diseases as well as asthma.
The suppression of the cellular target, interleukin-2-inducible T cell kinase, for blocking HIV replication may aid in developing new treatment modalities against the infection and also help in circumventing drug resistance.
Reference
1. Readinger JA, Schiralli GM, Jiang JK, et al. Selective targeting of ITK blocks multiple steps of HIV replication. Proc Natl Acad Sci U S A. 2008 May 6;105(18):6684-9.
2. François F, Klotman ME. Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. J Virol. 2003 Feb;77(4):2539-49.http://www.medinewsdirect.com/?p=475
New procedure adds weapon to fight HIV
July 17, 2008
Recommend (1)
National Institutes of Health research group has uncovered a new route for attacking the human immunodeficiency virus (HIV) that may offer a way to circumvent problems with drug resistance.
In findings published in the online edition of the Proceedings of the National Academy of Sciences, researchers report that they have blocked HIV infection in the test tube by inactivating a human protein expressed in key immune cells.
Most of the drugs now used to fight HIV, which is the retrovirus that causes acquired immune deficiency syndrome (AIDS), target the virus's own proteins. However, because HIV has a high rate of genetic mutation, those viral targets change quickly and lead to the emergence of drug-resistant viral strains.
Mutating problems
Doctors have tried to outmaneuver the rapidly mutating virus by prescribing multi-drug regimens or switching drugs. But such strategies can increase the risk of toxic side effects, be difficult for patients to follow and are not always successful.
Recently, interest has grown in attacking HIV on a new front by developing drugs that target proteins of human cells, which are far less prone to mutations than are viral proteins.
In the new study, Pamela Schwartzberg, M.D., Ph.D., a senior investigator at the National Human Genome Research Institute, part of NIH; Andrew J. Henderson, Ph.D., of Boston University; and their colleagues found that when they interfered with a human protein called interleukin-2-inducible T cell kinase (ITK) they inhibited HIV infection of key human immune cells, called T cells. ITK is a signaling protein that activates T cells as part of the body's healthy immune response.
When HIV enters the body, it infects T cells and takes over the activities of these white blood cells so that the virus can replicate. Eventually, HIV infection compromises the entire immune system and causes AIDS.
Tricking T cells
The new work shows that without active ITK protein, HIV cannot effectively take advantage of many signaling pathways within T cells, which in turn slows or blocks the spread of the virus.
In their laboratory experiments, the researchers used a chemical inhibitor and a type of genetic inhibitor, called RNA interference, to inactivate ITK in human T cells.
Then, the T cells were exposed to HIV, and the researchers studied the effects of ITK inactivation upon various stages of HIV's infection and replication cycle.
Suppression of ITK reduced HIV's ability to enter T cells and have its genetic material transcribed into new virus particles. However, ITK suppression did not interfere significantly with T cells' normal ability to survive, and mice deficient in ITK were able to ward off other types of viral infection, although antiviral responses were delayed.
For more information, see www3.niaid.nih.gov/healthscience/healthtopics/HIVAIDS/overview.
http://www.pioneerlocal.com/wauconda/lifestyles/health_family/1060277,on-AIDS-062608-s1.article
Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses. Author/s, J Forssell, Paschalis Sideras, ...
www.lu.se/o.o.i.s?id=12683&postid=238849 -
Trends in Immunology : Altering T-cell activation by targeting the ...
Targeting motifs within interleukin-2 inducible T-cell kinase (Itk) and potential for selectivity. The individual domains of Itk are indicated as PH ...
linkinghub.elsevier.com/retrieve/pii/S1471490603000711
Study Finds Potential New Therapeutic Target against HIV Infection ...
May 12, 2008 ... The suppression of the cellular target, interleukin-2-inducible T cell kinase, for blocking HIV replication may aid in developing new ...
www.medinewsdirect.com/?p=475
Tec Kinase Itk Forms Membrane Clusters Specifically in the ...
In particular, interleukin-2 inducible T cell kinase (Itk) plays an important role in modulating T cell development and activation. ...
www.jbc.org/cgi/content/abstract/281/50/38529
Human Protein May Offer Novel Target For Blocking HIV Infection ...
Apr 29, 2008 ... human protein called interleukin-2-inducible T cell kinase (ITK) they inhibited HIV infection of key human immune cells, called T cells. ...
huehueteotl.wordpress.com/.../ - 22k - Cached - Similar pages - Note this
Glossary terms : TEC-family kinases: regulators of T-helper-cell ...
Cyclophilin A is a peptidylprolyl isomerase that acts on a proline residue present in ITK (interleukin-2-inducible T-cell kinase). ...
www.nature.com/nri/journal/v5/n4/glossary/nri1591.html
Selective Itk inhibitors block T-cell activation and murine lung ...
Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors. [My paper] Jagabandhu Das, Joseph A Furch, Chunjian Liu, ...
lib.bioinfo.pl/pmid:15323564
Selective Itk Inhibitors Block T-Cell Activation and Murine Lung ...
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have ...
www.level1diet.com/97017_id
Bioorganic & Medicinal Chemistry Letters : Discovery and SAR of 2 ...
In summary, starting from a screening lead 1 with modest biochemical and cell potency we identified a series of potent and selective Itk inhibitors as ...
linkinghub.elsevier.com/retrieve/pii/S0960894X06001569
Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery ...
Three Mechanistically Distinct Kinase Assays Compared: Measurement of Intrinsic ATPase Activity Identified the Most Comprehensive Set of ITK Inhibitors. ...
lib.bioinfo.pl/pmid:17499505
Bioorg Med Chem Lett. 2007 Apr 25; : 17499505 (P,S,E,B,D)
Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors.
[My paper] Roger J Snow, Asitha Abeywardane, Scot Campbell, John Lord, Mohammed A Kashem, Hnin Hnin Khine, Josephine King, Jennifer A Kowalski, Steven S Pullen, Teresa Roma, Gregory P Roth, Christopher R Sarko, Noel S Wilson, Michael P Winters, John P Wolak, Charles L Cywin
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
(WO/2007/075255) MASTIC GUM COMPOSITION FOR USE AS A DIETARY ...
The herbal agent according to claim 6, wherein about 0.1% to about 50.0% of the composition further comprises one of or combinations of benzimidazole, ...
www.wipo.int/pctdb/en/wo.jsp?IA=WO2007075255&wo=2007075255&DISPLAY=CLAIMS -
Herb-drug interactions: Yin Zhi Huang and omeprazole
File Format: Microsoft Word - View as HTML
Herbal medicine Yin-zhi-huang induces both CYP3A4-mediated sulfoxidation and ... Omeprazole, a substitute benzimidazole derivative, belongs to a class of ...
www.hktmc.com/ChineseMedia/Magazine/Medicine/ajdmpk/AJDMPK-2006-3/asian6-3(206-213)(Fan%20L).do
http://www.google.com/search?hl=en&q=Benzimidazole+herb&start=10&sa=N
Chemical structure of Benzimidazole_chemical_structure
Benzimidazole
Systematic (IUPAC) name
1H-benzoimidazole
Synonyms
BI
Identifiers
PubChem 5798
Chemical data
Formula C7H6N2
Molar mass 118.136
Complete data
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. [1]
It is produced commercially as an parasiticide. The usual synthesis involves condensation of trimethylorthoformate and o-phenylenediamine:
C6H4(NH2)2 + HC(OCH3)3 ? C6H4N(NH)CH + 3 CH3OH
Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition metal complexes. They are often prepared by deprotonating an N,N'-disubstituted benzimidazolium salt at the 2-position with a base.[2][3]
See also
* Albendazole, a common use anthelmintic.
* Indole, an analog with CH in place of nitrogen in position 3.
* Purine, an analog with two additional nitrogen atoms in the six-membered ring.
* Simple aromatic rings
* Triclabendazole, most common drug against liver flukes
http://www.answers.com/benzimidazole?cat=technology
http://www.google.com/search?q=Benzimidazole+benzimidazole+
Triclabendazole
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Triclabendazole
Systematic (IUPAC) name
5-chloro-6- (2,3-dichlorophenoxy) -2-methylsulfanyl- 3H-benzoimidazole
Identifiers
CAS number 68786-66-3
ATC code P02BX04
PubChem 50248
Chemical data
Formula C14H9Cl3N2OS
Mol. mass 359.658
http://en.wikipedia.org/wiki/Triclabendazole
Triclabendazole (commercial name Fasinex) is a member of the Benzimidazole family of anthelmintics. The benzimidazole drugs share a common molecular structure, triclabendazole being the exception in having a chlorinated benzene ring but no carbamate group.
Triclabendazole displays high efficacy against both immature and adult liver fluke.
It is generally accepted that benzimidazoles like triclabendazole bind to beta-tubulin and prevent the polymerisation of the microtubules of which they are part.
http://www.google.com/search?q=Fasinex
Note
Novel potential anticancer agents derived from benzimidazole
El-Sebaii A. Ibrahim, A.-Mohsen M. E. Omar *, M. A. Khalil
Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
http://www3.interscience.wiley.com/journal/113291413/abstract
*Correspondence to A.-Mohsen M. E. Omar, Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
Keywords
Antineoplastic agents, potential - benzimidazole sulfonic esters and nitrogen mustards, synthesis and evaluation for antileukemic activity • Benzimidazole derivatives - sulfonic esters and nitrogen mustards, synthesis and evaluation for anticancer activity
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF9-4J8D8Y7-7&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6884e1d2b68ae0598c21c90ced88b238
Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors*
Kieron Brown{ddagger}, Joanna M. Long{ddagger}, Sarah C. M. Vial{ddagger}, Neesha Dedi{ddagger}, Nicholas J. Dunster{ddagger}, Suzanne B. Renwick{ddagger}, Adam J. Tanner{ddagger}, J. Dan Frantz§, Mark A. Fleming§, and Graham M. T. Cheetham{ddagger}¶
From the {ddagger}Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, United Kingdom and §Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139
Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fc{epsilon}. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.http://www.jbc.org/cgi/content/abstract/279/18/18727
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http://news.bbc.co.uk/1/hi/health/7541735.stm
HIV vaccine 'allows drug breaks'
Antiretroviral drugs are used to combat HIV
Scientists are testing a vaccine designed to give HIV patients a prolonged break from their regular medication without side effects.
The Aids 2008 conference in Mexico City was told 345 patients in 21 centres in the US and Europe will take part in the largest-ever trial of its kind.
The vaccine has been developed by a biotechnology company based in Norway, Bionor Immuno.
Results from the trial are due by the end of 2009.
A break from standard HIV therapy would potentially alleviate the adverse side effects associated with the drugs, and help delay the emergence of drug-resistant viruses, as well as providing substantial savings for health care services.
Dr Barry Peters, of Kings College London, is leading the research in the UK.
He said: "A successful immunotherapeutic HIV vaccine would give patients and doctors enormous advantages over current treatments, both in developed and developing countries.
"Even if this vaccine is not the final answer, it could help the march towards a successful immunotherapeutic HIV vaccine."
The vaccine, which works by stimulating an immune system response, has already been tested in two small trials on 11 and 38 HIV patients with promising results.
The majority of patients were able to refrain from taking their usual antiretroviral therapy (ART) for an average period of 31 months.
During this time their level of key infection-fighting CD4+ cells remained high above the level they had before they started taking ART.
At a follow up 44 months after treatment interruption, 34% of the patients were still not back on ART.
Some patients were still off ART five years after the trial was completed.
ART cannot usually cannot be interrupted for more than three to four months without side effects.
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I HAD TO DO A DOUBLE TAKE WITH THIS HEADLINE -- perhaps if we would have used a plug in first place we wouldn't have hiv --- lol --- why is "adapter plug" in quote marks in this article--------------- are there any English majors who CAN explain this funny breakthrough grammatically --- but it does make sense scientifically, even i can understand it right away ---------------------------------------------------------
'Adapter plug' to turn antibodies into HIV killers
* 22:00 11 August 2008
* NewScientist.com news service
* Nora Schultz
An "adapter plug" molecule that transforms spare antibodies into HIV killers could provide a new way to treat AIDS and other viruses.
The antibodies targeted by the molecule are called anti-gal. They are naturally present in humans and typically make up 1% of all antibodies in the blood.
They help to fight Salmonella and Escherichia coli by binding to a sugar on the bacteria's surfaces. But unless you are fighting a serious infection, most go spare.
"Most of the time these antibodies don’t do much, so we thought it would be useful if we could teach them to recognise HIV," says Anders Vahlne at the Karolinska Institute in Stockholm, Sweden.
Antibody engineering
His team created a molecule with the sugar group that anti-gal recognises on one end. On the other end, they attached a string of atoms that mimics part of a receptor, found on human immune cells, that binds to HIV.
The result is a molecule that binds to both anti-gal and HIV. It acts like a kind of adapter plug for the antibodies, allowing their innate cell-destroying machinery to be unleashed on HIV-infected cells.
"The antibodies block the interaction between virus and host cell, recruit molecules that will destroy infected cells, and alert killer cells that will eat them," says Vahlne, who also does research for the company TriPep in Stockholm, which hopes to commercialise the idea.
Virus roadblock
When his team added HIV viruses to human cells that had been primed with the adapter molecules and anti-gal antibodies, almost 90% of the viruses were unable to infect the cells.
The adapters must still be tested in HIV-infected mice but Rowena Johnston of AIDS research foundation amfAR says the work shows how "we might be able to use the innate immune system in a surprising and intriguing way".
Vahlne is also tweaking the molecules to bind to MRSA, responsible for many fatal hospital infections.
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http://www.jem.org/cgi/content/abstract/165/3/693
The human natural anti-Gal IgG. III. The subtlety of immune tolerance in man as demonstrated by crossreactivity between natural anti-Gal and anti-B antibodies
U Galili, J Buehler, SB Shohet and BA Macher
A well-defined antigen/antibody system was used to evaluate the effect of immune tolerance on the spectrum of specificities of natural antibodies. The antibody used in this study, anti-Gal, is a naturally occurring, polyclonal IgG that constitutes 1% of the circulating IgG in humans. We have previously shown that anti-Gal, purified from AB sera, specifically interacts with glycosphingolipids bearing a Gal alpha 1---- 3Gal epitope, but not with the closely related B antigen in which the penultimate galactose of the Gal alpha 1----3Gal epitope is fucosylated Gal alpha 1----3(Fuc alpha 1----2)Gal. This narrow specificity was assumed to be the result of an effective immune tolerance mechanism that prevents the expression of antibody clones that can recognize both the Gal alpha 1----3Gal and the self B epitopes. If the assumption that immune tolerance determines the range of anti-Gal specificity is correct, then anti-Gal from individuals lacking the B antigen (A and O blood types) would be expected to interact with both Gal alpha 1---- 3Gal and Gal alpha 1----3(Fuc alpha 1----2)Gal epitopes. In this study, anti-Gal from the serum of individuals of various blood types was purified by affinity chromatography on Gal alpha 1----3Gal adsorbent and tested for its reaction with the B antigen. Whereas anti-Gal from AB and B individuals only reacted with Gal alpha 1----3Gal epitopes, anti-Gal from A and O individuals reacted with both Gal alpha 1----3Gal and B epitopes. Furthermore, it was determined that the majority of anti-B reactivity in A and O individuals is in fact anti-Gal antibodies capable of recognizing both Gal alpha 1----3Gal and B epitopes. It can be concluded from these results that immune tolerance accurately controls the spectrum of natural antibody specificities by preventing the production of antibody clones that can interact with self antigens.
http://www.google.com/search?q=anti-gal
http://www.google.com/search?hl=en&q=anti-gal+hiv&btnG=Search
lots here to look at
very interesting
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Where are you Bima?
We need your research news
:)
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'Adapter plug' to turn antibodies into HIV killers
* 22:00 11 August 2008
* NewScientist.com news service
* Nora Schultz
An "adapter plug" molecule that transforms spare antibodies into HIV killers could provide a new way to treat AIDS and other viruses.
The antibodies targeted by the molecule are called anti-gal. They are naturally present in humans and typically make up 1% of all antibodies in the blood.
They help to fight Salmonella and Escherichia coli by binding to a sugar on the bacteria's surfaces. But unless you are fighting a serious infection, most go spare.
"Most of the time these antibodies don’t do much, so we thought it would be useful if we could teach them to recognise HIV," says Anders Vahlne at the Karolinska Institute in Stockholm, Sweden.
Antibody engineering
His team created a molecule with the sugar group that anti-gal recognises on one end. On the other end, they attached a string of atoms that mimics part of a receptor, found on human immune cells, that binds to HIV.
The result is a molecule that binds to both anti-gal and HIV. It acts like a kind of adapter plug for the antibodies, allowing their innate cell-destroying machinery to be unleashed on HIV-infected cells.
"The antibodies block the interaction between virus and host cell, recruit molecules that will destroy infected cells, and alert killer cells that will eat them," says Vahlne, who also does research for the company TriPep in Stockholm, which hopes to commercialise the idea.
Virus roadblock
When his team added HIV viruses to human cells that had been primed with the adapter molecules and anti-gal antibodies, almost 90% of the viruses were unable to infect the cells.
The adapters must still be tested in HIV-infected mice but Rowena Johnston of AIDS research foundation amfAR says the work shows how "we might be able to use the innate immune system in a surprising and intriguing way".
Vahlne is also tweaking the molecules to bind to MRSA, responsible for many fatal hospital infections.
this is also very very interesting and should be posted on more
another peptide, and interesting genetic discovery will be announced at gallo's conference in September - the rate of discovery is EXPONENTIAL in science as the human genes reveal secrets
the link to entire article is worth a read -- perhaps this should have a new post because not perfectly related to siRNA
Viral Genetics, Inc. Unveils Potential Mechanism of Action in HIV/AIDS Research, Accepted to Present Findings at Prestigious IHV Meeting
Team Welcomes Attendees to Poster Session to Discuss Findings, Which Could Lead to Inexpensive, Effective HIV Therapy, and May Be Applicable to Autoimmune Diseases
Last update: 2:02 p.m. EDT Aug. 19, 2008
AZUSA, Calif., Aug 19, 2008 (BUSINESS WIRE) -- Viral Genetics, Inc. (Other OTC:VRAL), a biotechnology company that discovers and develops immune-based therapies, today unveiled a new theory regarding a potential mechanism of action, which could advance HIV/AIDS research and the development of an inexpensive, effective therapy for HIV. The study team says some of the study findings may also be applicable to autoimmune disease. Viral Genetics has been accepted by the Institute of Human Virology (IHV) to unveil and discuss its new model and findings at IHV's 11th Annual International Meeting in an interactive poster session. The prestigious conference, founded by Dr. Robert C. Gallo, who co-discovered HIV as the cause of AIDS and developed the first HIV blood test, will take place September 11-13th in Baltimore, Maryland. For more information on the conference, visit www.ihv.org http://www.marketwatch.com/news/story/viral-genetics-inc-unveils-potential/story.aspx?guid={1E990E99-A89F-4DF4-B329-C6D805BFE087}&dist=hppr
Viral Genetics has and continues to use TNP-1, a mixture of peptides derived from thymic histones, to research HIV/AIDS. When used in six international human clinical trials, including a double blind placebo controlled study in South Africa, results indicated that 25-35% of the HIV-infected population exhibited significantly reduced viral load and clinical improvement. During in vitro research, the study group found that individual peptides in the TNP mixture can bind to antigen-presenting cells and may be able to redirect the immune response. The long-term goal of the study is to obtain an IND for testing the newly identified and synthesized peptides or "targeted peptides" that can appropriately redirect the immune response to HIV.
"Our findings suggest that, with the proper predictions, we can synthesize targeted peptides to treat people with different types of MHC alleles providing potentially an inexpensive, biologically active therapy for HIV," added Newell.
The Immune Response to HIV: Friend or Foe?
"While the results in human clinical trials are promising, the challenge has been identifying the mechanism and the active component of the mixtures," said Newell. Targeted Peptides as a Therapeutic Strategy for HIV
Viral Genetics' working hypothesis is that treatment with custom-designed and predicted "targeted peptides," which will bind to the surface of the right white cells (antigen presenting cells) could, in turn, activate specific Tregs (a special category of T cells widely reported to dampen chronic inflammation). Dampening inflammation may be required to decrease the number of activated CD4 T cells that can become virally infected. The hypothesis is supported by recent findings showing that there is a correlation between the presence and numbers of Tregs and the length of time between initial infection with HIV and full-blown AIDS .
"We are very excited after many years of research to finally have discovered what appears to be the promising mechanism of action that could optimize our treatment to its fullest potential. This also opens the door to a paradigm shift in thinking around HIV/AIDS therapies," said Monica Ord, SVP of corp. development and communications for Viral Genetics.
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Black raspberries slow cancer by altering hundreds of genes
from Science Blog - by BJS
New research strongly suggests that a mix of preventative agents, such as those found in concentrated black raspberries, may more effectively inhibit cancer development than single agents aimed at shutting down a particular gene. http://www.scienceblog.com/cms/black-raspberries-slow-cancer-altering-hundreds-genes-17231.html
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Shouldn't this be in the "Research news" part of the forum?
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Shouldn't this be in the "Research news" part of the forum?
Yeah Betty,
I was also wondering what the connection was between this and HIV as well.
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Black raspberries slow cancer by altering hundreds of genes
from Science Blog - by BJS
2,200 (2,261?) genes activity affected by a chemical carcinogen in rats, 460 (462?) restored by the berries, 53 genes "that may play a fundamental role in early [rats' esophageal] cancer [caused by N-nitrosomethylbenzylamine] development"... And the National Cancer Institute pays for these stupid, useless lottery numbers???
New research strongly suggests that a mix of preventative agents [...] may more effectively inhibit cancer development than single agents aimed at shutting down a particular gene.
http://www.scienceblog.com/cms/black-raspberries-slow-cancer-altering-hundreds-genes-17231.html
Surprisingly smart conclusion!
Poor us, cancer and AIDS researchers are really at their wits' end!
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I love raspberries.
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Where is Bimazek and why is he not posting research news for us. Don't make me search the US for you Bim, I expect some kind of news Tomorrow.
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good news, they are working on a complete map of Immunological Genome Project
top universities
top funding
top people
powerful computers
this should help
2008 October
The Immunological Genome Project: networks of gene expression in immune cells
The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune cells
Tracy S P Heng12, Michio W Painter12, The Immunological Genome Project Consortium,
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Computer Science, Stanford University, Stanford, California 94305, USA.
http://www.nature.com/ni/journal/v9/n10/abs/ni1008-1091.html
Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02115, USA, and Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Section on Immunology and Immunogenetics, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.
Department of Microbiology & Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, California 94143, USA.
Department of Biomechanical Engineering and Center for BioDynamics, Boston University, Boston, Massachusetts 02215, USA.
Division of Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Principal investigator.
Tracy S.P. Heng and Michio W. Painter are in the Section on Immunology and Immunogenetics, Joslin Diabetes Center & Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
e-mail: immgen@joslin.harvard.edu
Abstract
The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune cells
http://www.nature.com/ni/journal/v9/n10/abs/ni1008-1091.html
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one step closer ------ APOBEC-3G Body's Anti-HIV Drug Explained
ScienceDaily (Oct. 12, 2008) — Humans have a built-in weapon against HIV, but until recently no one knew how to unlock its potential.
That would unlock humans' innate ability to fight HIV. "We were born with it, and it's there waiting," Chen said.
http://www.sciencedaily.com/releases/2008/10/081012164445.htm
Body's Anti-HIV Drug Explained
ScienceDaily (Oct. 12, 2008) — Humans have a built-in weapon against HIV, but until recently no one knew how to unlock its potential.
A study published online by the journal Nature reveals the atomic structure of this weapon – an enzyme known as APOBEC-3G – and suggests new directions for drug development.
APOBEC-3G is present in every human cell. It is capable of stopping HIV at the first step of replication, when the retrovirus transcribes its RNA into viral DNA.
The study's authors, led by Xiaojiang Chen of the University of Southern California, were able to show the atomic structure of the active portion of APOBEC-3G.
The discovery suggests how and where the enzyme binds to the viral DNA, mutating and destroying it.
"We understand how this enzyme can interact with DNA," said Chen, a professor of molecular and computational biology at USC. "This understanding provides a platform for designing anti-HIV drugs."
If APOBEC-3G works so well, why do people get AIDS? Because the HIV virus has evolved to encode the protein Vif, known as a "virulence factor," that blocks APOBEC-3G.
With APOBEC-3G out of the way, the RNA of the HIV virus can be successfully transcribed to viral DNA, an essential step for infection and for producing many more HIV viruses.
Chen said his group's research offers important clues on where Vif binds to APOBEC-3G. The knowledge could be used to design drugs that would prevent Vif from binding and allow APOBEC-3G to do its job, Chen said.
That would unlock humans' innate ability to fight HIV. "We were born with it, and it's there waiting," Chen said.
In addition to fighting HIV, APOBEC-3G can inhibit the Hepatitis B virus. Other members of the APOBEC family serve important roles in antibody maturation, fat metabolism and heart development.
Mapping the structure of APOBEC-3G at the atomic level is a goal that "has been sought after worldwide because of its significance," Chen said.
Chen's co-authors were USC graduate students and postdoctoral researchers Lauren Holden, Courtney Prochnow, Y. Paul Chang, Ronda Bransteitter, Linda Chelico and Udayaditya Sen; Raymond Stevens, professor of molecular biology at The Scripps Research Institute; and Myron Goodman, professor of molecular biology at USC.
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Bim,
Nice find!
Here's more:
http://www.retrovirology.com/content/5/1/72
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Where is Bimazek? !!!!
??? we need more research news....
:D