Bimazek's Research News

[bimazek]

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).

[Ann]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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."

[bimazek]

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.

[bimazek]

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.]

[bimazek]

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.

[shadowfluid]

Best. Thread. Ever. Don't know why I'm just discovering it now. More more!

[bimazek]

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/

[bimazek]

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

[bimazek]

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.

[bimazek]

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

[bimazek]

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."

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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

[bimazek]

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/

[bimazek]

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%).

[bimazek]

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

[bimazek]

“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

[bimazek]

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.

[bimazek]

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.

[bimazek]

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

[georgep77]

Where are you Bima?

          We need your research  news

                                     

                                           

[bimazek]

'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.

[bimazek]

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

[BT65]

Shouldn't this be in the "Research news" part of the forum?

[sharkdiver]

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.

[leit]

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!

[Miss Philicia]

I love raspberries.

[datdude]

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.

[bimazek]

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

[bimazek]

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.

[veritas]

Bim,

Nice find!

Here's more:


http://www.retrovirology.com/content/5/1/72

[georgep77]

Where is Bimazek?    !!!!

                we need more research news....