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Author Topic: Innate Immune Response to HIV  (Read 5090 times)

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Offline Mishma

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Innate Immune Response to HIV
« on: January 22, 2013, 02:22:03 PM »
Animals have evolved two overlapping responses to infection, cancers and other threats to the host. One is the much talked about Adaptive Immune Response which includes both antibodies and cells that kill target cells either by direct attack or by engulfing them and destroying them in intracellular reservoirs. Much of the discussion on these boards involve these processes, however an evolutionary older response is one called the innate immune response-which also targets infected cells, and intracellular viral RNA and DNA. The HIV virus has miraculously escaped destruction by these two powerful arms of our immune systems. I have provided a link to HIV and innate immune system. The entire review is free.

Abstract
The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis.


http://www.retrovirology.com/content/7/1/54
« Last Edit: January 22, 2013, 02:36:40 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #1 on: January 22, 2013, 08:29:13 PM »
Another excellent article that put ALL viruses in context to our genome.

http://www.ncbi.nlm.nih.gov/pubmed/22999945


Immunity. 2012 Sep 21;37(3):389-98. doi: 10.1016/j.immuni.2012.08.011.
Innate immune recognition of HIV-1.
Iwasaki A.
Source
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu

Abstract
In contrast to the extraordinary body of knowledge gained over the past three decades on the virology, pathogenesis, and immunology of HIV-1 infection, innate sensors that detect HIV-1 had remained elusive until recently. By virtue of integration, retroviridae makes up a substantial portion of our genome. Thus, immune strategies that deal with endogenous retroviruses are, by necessity, those of self-preservation and not of virus elimination. Some of the principles of such strategies may also apply for defense against exogenous retroviruses including HIV-1. Here, I highlight several sensors that have recently been revealed to be capable of recognizing distinct features of HIV-1 infection, while taking into account the host-retrovirus relationship that converges on avoiding pathogenic inflammatory consequences.

Copyright © 2012 Elsevier Inc. All rights reserved.

There is another concept in immunology called Tolerance. I think this applies here with respect to our HIV and chronic immune activation. Mine, as you know is in high gear. Rather than try to destroy the HIV we need to find it a quite home to live in our DNA like the other viruses that cohabitate in us. Less virulent, less immuno-stimulatory, ideally less toxic drugs. Taming the beast may be just as effective as trying to destroying it.
« Last Edit: January 22, 2013, 08:32:08 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #2 on: February 16, 2013, 02:26:10 PM »
This a pretty esoteric article, where I don't expect people to get bogged down on the detail. I post this as yet another example of how our innate immune system  and in this instance how it modulates inflammation in the CNS, this time through through a neurotransmitter receptor, Dopamine D2 on astrocytes. Astrocytes harbor HIV in the brain but are not thought to be a big source of HIV replication within the CNS (see my other posts on this subject). They do make life miserable for their surrounding neurons by secreting inflammatory and apoptotic chemical messengers.

This receptor, for what ever reason, appears to be downregulated in a number of diseases of the CNS, including Parkinsons and HIV.

CRYAB is one form of general group of proteins called chaperones whose job is, as the name would imply, to  "take care of" or accompany other proteins as they are internalized (in the case of the this receptor) or make their way through other cellular  pathways. They do this by a number of mechanisms such as: prevention of degradation, proper trafficking and recycling.

Neuroimmflammation has been the bane of my existence since I first became aware of my symptoms of HIV infection, some 28+ years ago.

 
http://www.nature.com/nature/journal/v494/n7435/full/nature11748.html

Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin

Wei Shao,    Shu-zhen Zhang,    Mi Tang,    Xin-hua Zhang,    Zheng Zhou,    Yan-qing Yin,    Qin-bo Zhou,    Yuan-yuan Huang,    Ying-jun Liu,    Eric Wawrousek,    Teng Chen,    Sheng-bin Li,    Ming Xu, Jiang-ning Zhou,    Gang Hu    & Jia-wei Zhou
AffiliationsContributionsCorresponding author
Nature 494, 90–94 (07 February 2013) doi:10.1038/nature11748
Received 01 August 2011 Accepted 07 November 2012 Published online 16 December 2012
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Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through αB-crystallin (CRYAB), which is known to suppress neuroinflammation1, 2. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity3. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.
« Last Edit: February 16, 2013, 02:39:34 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #3 on: February 16, 2013, 03:03:09 PM »
Perhaps deserving of a separate topic, I'll keep these in this thread because the effects of microRNAs are thought to be mediated by aspects of our Innate Immune System. The first abstract deals with a drug that is being used in the treatment of Hep C, a bug that many of us can relate to.


Discovering the first microRNA-targeted drug

http://jcb.rupress.org/content/199/3/407.abstract

Morten Lindow1,2 and Sakari Kauppinen2,3
+ Author Affiliations
1Department of Biology, The Bioinformatics Centre, University of Copenhagen, DK-2200 Copenhagen, Denmark
2Santaris Pharma, DK-2970 Hørsholm, Denmark
3Department of Health Science and Technology, Aalborg University Copenhagen, DK-2450 Copenhagen SV, Denmark
Correspondence to Sakari Kauppinen: sk@bio.aau.dk
MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery programs that focus on developing miRNA-based therapeutics. The most advanced of these programs targets the liver-expressed miRNA-122 using the locked nucleic acid (LNA)–modified antisense oligonucleotide miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for treatment of hepatitis C virus (HCV) infection.


http://www.nature.com/ni/journal/v14/n3/full/ni.2537.html?WT.ec_id=NI-201303


MicroRNAs as mediators of viral evasion of the immune system

Bryan R Cullen
Nature Immunology 14, 205–210 (2013) doi:10.1038/ni.2537
Received 05 November 2012 Accepted 29 December 2012 Published online 15 February 2013
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Abstract
Abstract    Author information
Cellular microRNAs serve key roles in the post-transcriptional regulation of almost every cellular gene-regulatory pathway, and it therefore is not surprising that viruses have found ways to subvert this process. Several viruses encode microRNAs that directly downregulate the expression of factors of the innate immune system, including proteins involved in promoting apoptosis and recruiting effector cells of the immune system. Viruses have also evolved the ability to downregulate or upregulate the expression of specific cellular miRNAs to enhance their replication. This Review provides an overview of the present knowledge of the complex interactions of viruses with the microRNA machinery of cells.
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Mishma

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Innate Immune Response to HIV
« Reply #4 on: February 19, 2013, 10:00:12 PM »
Yet another example of an innate immune response. The cells in our body are programed to self destruct if things go awry or when their jobs are completed. HIV short circuits this process by the binding of it's Nef protein to some of the cells machinery, in this case a key protein in autophagy. This self destructive process is often referred to as programmed cell death or apoptosis. Both the innate and adaptive immune responses can induce damaged or infected cells to undergo this process.

In this paper the authors  think they have identified the cells own inhibitor of autophagy and in doing so, in cell culture, have used peptides (short stretches of amino acids) that inhibited viral replication and induced apoptosis.

http://stke.sciencemag.org/cgi/content/abstract/sigtrans;6/263/ec45

Sci. Signal., 19 February 2013
Vol. 6, Issue 263, p. ec45
[DOI: 10.1126/scisignal.2004078]

EDITORS' CHOICE

Cell Biology
Fighting Disease with Autophagy

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Autophagy is a degradative process through which cells survive periods of nutrient scarcity or dispose of defective proteins or organelles. The removal of viruses and other pathogens by autophagy is an important aspect of the immune response, and some viruses, including HIV-1, evade elimination by inhibiting autophagy (see commentary by García-Sastre). Noting that the HIV-1 protein Nef binds to and inhibits the autophagy protein beclin 1, Shoji-Kawata et al. used immunoprecipitation assays to identify an 18–amino acid residue region of beclin 1 that was required for this physical association. The authors linked this sequence to the protein transduction domain of the HIV-1 protein Tat to generate the cell-permeable peptide Tat–beclin 1. Compared to a Tat-linked scrambled peptide (Tat-scrambled), the Tat–beclin 1 peptide induced autophagy in various cell lines through a canonical mechanism that required components downstream of beclin 1. Biochemical and mass spectrometry analyses revealed that Tat–beclin 1, but not Tat-scrambled, was a binding partner for Golgi-associated plant pathogenesis–related protein 1 (GAPR-1). Knockdown of GAPR-1 in HeLa cells led to enhanced basal autophagosome formation in the absence of Tat–beclin 1, suggesting that GAPR-1 is an endogenous inhibitor of autophagy. Microscopic analysis showed that endogenous beclin 1 was sequestered to the Golgi by GAPR-1; however, in the presence of the Tat–beclin 1 peptide, beclin 1 redistributed to the cytoplasm. Pretreatment of cells with Tat–beclin 1, but not Tat-scrambled, before infection with various viruses, including HIV-1 and West Nile virus (WNV), led to decreased viral replication. In addition, Tat–beclin 1, but not Tat-scrambled, reduced the amounts of protein aggregates in a cellular model of huntingtin protein accumulation. Immunohistochemical analysis showed that Tat–beclin 1 induced autophagy in mice without toxic effects. Finally, administration of Tat–beclin 1 to mice infected with WNV or chikungunya virus led to decreased viral replication and increased survival. Together, these data identify GAPR-1 as an endogenous inhibitor of autophagy and suggest that peptide-mediated induction of autophagy may have therapeutic benefit in various human diseases.

S. Shoji-Kawata, R. Sumpter Jr., M. Leveno, G. R. Campbell, Z. Zou, L. Kinch, A. D. Wilkins, Q. Sun, K. Pallauf, D. Macduff, C. Huerta, H. W. Virgin, J. B. Helms, R. Eerland, S. A. Tooze, R. Xavier, D. J. Lenschow, A. Yamamoto, D. King, O. Lichtarge, N. V. Grishin, S. A. Spector, D. V. Kaloyanova, B. Levine, Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013). [PubMed]

A. García-Sastre, Beneficial lessons from viruses. Nature 494, 181–182 (2013). [PubMed]

Citation: J. F. Foley, Fighting Disease with Autophagy. Sci. Signal. 6, ec45 (2013).
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline mecch

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Re: Innate Immune Response to HIV
« Reply #5 on: February 19, 2013, 10:25:44 PM »
Neuroimmflammation has been the bane of my existence since I first became aware of my symptoms of HIV infection, some 28+ years ago.

How does this manifest?  Neuropathy?
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #6 on: February 20, 2013, 12:35:34 AM »
Auto-immune encephalitis in the CNS and Motor Predominant Polyneuropathy with conduction block in my peripheral nervous system.

I'm in remission for other auto-immune diseases: Thrombocytopenia and Hemolytic Anemia and Graves disease.

If you guys and gals don't mind (since my mind is going) I'm going to keep posting to this thread articles of interest that involve our innate immune response, which has been given short shrift not only in these forums, but within the larger medical community as well. Even the latest gene targeting technology (superior to the synthetic zinc finger nucleases) comes from new work involving our innate immunity research. 
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline oksikoko

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Re: Innate Immune Response to HIV
« Reply #7 on: February 21, 2013, 06:43:57 AM »
If you guys and gals don't mind (since my mind is going) I'm going to keep posting to this thread articles of interest that involve our innate immune response, which has been given short shrift not only in these forums, but within the larger medical community as well. Even the latest gene targeting technology (superior to the synthetic zinc finger nucleases) comes from new work involving our innate immunity research. 

I certainly don't mind. What I can understand is fascinating. I only wish I had started reading about this earlier. It's like a foreign language, and I'm far beyond optimal age, unfortunately. Do you understand all of this?

In the most recent abstract you posted, I lost the thread after "Golgi-associated plant pathogenesis–related protein" but found it after "GAPR-1 is an endogenous inhibitor of autophagy." I mean, I know what all of those words mean except Golgi, and it's been around for over 100 years, so there's really no excuse. If you'll indulge me, let me try to put this in layman's terms without reading your synopsis, which would be cheating. One step at a time:

OK, so part of our immune system concerns itself with "eating" our own cells during nutrient scarcity. This is called, naturally, autophagy, and the things that do it are called autophagosomes (auto [self] phago [eating] somes [bodies]).

You wouldn't want this process to be unregulated, because, much as unregulated cell division causes cancer, unregulated cannibalism would lead to the untimely death of the organism. So, we have this nice thing called a Golgi-associated plant pathogenesis–related protein 1, or GAPR-1 for short. The Golgi is an organelle (chic!) which is similar to the dude who boxes your purchases before Amazon ships them to you, except it packages up proteins before they leave the cell. Pathogenesis has to do with the origin of disease, but what "plant" has to do with it is beyond me. Let's just accept that GAPR-1 is a protein that works at the Golgi and smokes cigarettes out back on its lunch break. Whenever GAPR-1 is mucking about, autophagy seems to slow down, which is something we noticed when we knocked GAPR-1 down in HeLa cells, whatever those are, and saw an increase in the number of autophagosomes running around free in the cytoplasm. We aren't entirely sure why, but inspection under a microscope, shows that beclin-1, a real high class autophagosome, likes to slum behind the Golgi smoking cigarettes with GAPR-1 instead of eating cells. If you ask me, it's afraid to eat because GAPR-1 makes horrible comments about its figure, but I'm not one to gossip. In any event, it's important to remember that this is not necessarily bad, since we don't want unregulated autophagy, nor do we want to interfere in their relationship, however codependent it may be.

Back to our story. In times of plenty, autophagy serves not only as a way to recycle nutrients but also kicks in as an immune response against cells which have been invaded by foreign bodies. HIV is a tricky little bastard, though, and has a defense against autophagosomes: one of its proteins, Nef, binds to the aforementioned beclin-1. With the cells supply of beclin-1 bound by HIV or occupied by GAPR-1, the total amount of autophagy goes down and the viral invader continues replicating in compromise (and uneaten) cells. Oh, noes!

Shoji-Kawata and his buddies used a fancy method to figure out where HIV-1 had bound beclin-1. With this information and an HIV protein called Tat, they reverse engineered something called Tat-beclin-1. It's similar to beclin-1, but has the figure of someone who never gave birth to four kids and who gets weekly botox treatments. There's also something called "tat-scrambled" though I don't get its relevance to the plot, so I'll ignore it.

So, GAPR-1 finds this Frankenstein peptide, Tat-beclin-1, irresistible and starts smoking with it instead of plain Jane beclin-1, who frankly should hit the gym more. Beclin-1 is completely torn up by this and spends its evenings bingeing on virus-flavored cells and old Bette Davis movies. So by pimping Tat-beclin-1 out to GAPR-1, we can indirectly increase the number of virus-infected cells that get eaten.

Shoji-Kawata and his pals tried introducing Tat-beclin-1 into cells of healthy mice, and it reduced replication of consequently introduced viruses. Ones you've heard of, like West Nile, and ones you can't spell, like chikungunya. There seem to be no toxic effects, so they're guessing this will work in people to increase overall autophagy, decrease overall viral replication and increase survival rates.

Please tell me something here is correct. If nothing else, it's made me want Haagen Dazs, and it's nearly time for Stribild. Stribild loves fat, and I so rarely give it to him. Everyone wins except science.

The end.
Code: [Select]
2014-??-??: off treatment  ☣ VL (?)              ☣ CD4 (?)
2013-10-03:                ☣ VL (=) undetectable ☣ CD4 (+) 1105
2013-05-23:                ☣ VL (=) undetectable ☣ CD4 (-) 945
2013-02-25:                ☣ VL (-) undetectable ☣ CD4 (+) 1123
2012-12-16: Enter Stribild
2012-11-20: HIV+           ☣ VL (→) 132,683      ☣ CD4 (→) 920
2012-04-01: HIV-
Dates in this signature file conform to ISO 8601. ;-)

If no one complains, nothing will ever change.

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #8 on: February 21, 2013, 10:51:09 AM »
Outstanding synopsis! You did a heck of a lot better than I did in describing this process and paper. And of course it is a specialized language. There are articles in Science and Nature that are  way outside my field and, in general, I don't have a clue what they are talking about.

 Do I understand all of it, heck no, primarily since I've been out of academia now for over 8 years and the field is evolving rapidly. Also because I don't subscribe to the journal and only get the abstract via my subscription to Science Magazine.To fully comprehend the results you would have to study the methods and other sections of the full paper

A great deal of redundancy is build into our immune system which HIV seems to be able to circumvent. Autophagy and Apoptosis, to my mind, is the systems option of last resort and it too seems to be thwarted in many cells, for a variety of reasons.

If you haven't already try tackling that review I posted further up the post. As a review it is a little more digestable than this paper.
« Last Edit: February 22, 2013, 12:26:54 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline mitch777

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Re: Innate Immune Response to HIV
« Reply #9 on: February 21, 2013, 12:13:34 PM »
Please pardon my intrusion into this thread, but I can't help myself in commenting on Oski's "story".
Scientific research is beyond my pay grade. ???
The character development and personal antidotes had me rolling on the floor.
I still don't understand it and will have to wait for the movie to come out.
Thanks for the laughs! :)
32 years hiv+ (oct. 2013) with a curtsy.

Offline Jmarksto

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Re: Innate Immune Response to HIV
« Reply #10 on: February 21, 2013, 03:56:26 PM »
Oks; Great translation and good story!  Like most translations, I have no idea how accurate it is.

JM
03/15/12 Negative
06/15/12 Positive
07/11/12 CD4 790          VL 4,000
08/06/12 CD4 816/38%   VL 49,300
08/20/12 Started Complera
11/06/12 CD4   819/41% VL 38
02/11/13 CD4   935/41% VL UD
06/06/13 CD4   816/41% VL UD
10/28/13 CD4 1131/45%  VL 25
02/25/14 CD4   792/37%  VL UD
07/09/14 CD4 1004/39%   VL UD

Offline Dr.Strangelove

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Re: Innate Immune Response to HIV
« Reply #11 on: February 22, 2013, 06:37:10 AM »
Great synopsis!

Btw, in case you are still wondering what HeLa cells are: link
It's not really relevant in this context, just a standard cell line that's used in all kinds of research. You may wonder why they use cancer cells for HIV research. The answer is simply because they keep replicating endlessly and that's useful.

Offline oksikoko

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Re: Innate Immune Response to HIV
« Reply #12 on: February 22, 2013, 08:15:13 AM »
Btw, in case you are still wondering what HeLa cells are: link
It's not really relevant in this context, just a standard cell line that's used in all kinds of research. You may wonder why they use cancer cells for HIV research. The answer is simply because they keep replicating endlessly and that's useful.

Thanks! It turns out I know more about HeLa cells than I thought I did but had forgotten the name. I listen to a lot of NPR podcasts, and I knew it would come in handy someday... ;)

http://www.npr.org/templates/story/story.php?storyId=123651144
http://www.npr.org/2011/03/18/134622044/tracing-the-immortal-cells-of-henrietta-lacks
Code: [Select]
2014-??-??: off treatment  ☣ VL (?)              ☣ CD4 (?)
2013-10-03:                ☣ VL (=) undetectable ☣ CD4 (+) 1105
2013-05-23:                ☣ VL (=) undetectable ☣ CD4 (-) 945
2013-02-25:                ☣ VL (-) undetectable ☣ CD4 (+) 1123
2012-12-16: Enter Stribild
2012-11-20: HIV+           ☣ VL (→) 132,683      ☣ CD4 (→) 920
2012-04-01: HIV-
Dates in this signature file conform to ISO 8601. ;-)

If no one complains, nothing will ever change.

Offline Mishma

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Innate Immune Response to HIV
« Reply #13 on: February 27, 2013, 12:40:26 PM »
http://www.nature.com/nmeth/journal/v10/n3/full/nmeth.2389.html?WT.ec_id=NMETH-201303

Cas proteins are endonuclease proteins that are a part of the cells innate immune response. They cut and attack foreign DNA that has been inserted into the host genome. Much like Zinc-Finger nucleases, the CRISP system nucleases, use an endonuclease, but rather than using proteins to guide the enzyme to its target this system uses complimentary RNA molecules to its job. As with the ZFN's one is concerned with "off-target" mutations (it cuts where you don't want it to cut) and on target disruptive mutations.

Targeted gene modification can be guided by programmable RNA in bacteria, zebrafish and mammalian cells.

Humble creatures, prokaryotes and viruses, have an illustrious history of providing biologists with molecular tools. Where, after all, would molecular biology—or for that matter, all of genomics—be without restriction endonucleases or DNA polymerases? And, as a recent flurry of papers reporting RNA-guided genome engineering demonstrates, the bacteria are still at it.

The clustered, regularly interspaced, short palindromic repeats (CRISPR) system is a component of bacterial and archaeal immunity. The CRISPR-associated (Cas) endonuclease cleaves foreign nucleic acids, directed to its target sequence by two small RNAs. In work published last year, researchers showed that the CRISPR-Cas system of Streptococcus pyogenes could be programmed to direct in vitro cleavage of desired target sequences. This raised the possibility that the approach could be used for targeted gene editing in vivo. With an almost startling rapidity, five recently published papers now show that it can.
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline scotty54

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Re: Innate Immune Response to HIV
« Reply #14 on: February 27, 2013, 06:13:31 PM »
Your post keeps bringing me back to read more.  Now I know what pathogenisis means.  Amazing research.
I may not agree with you, but will always defend your right to disagree.

Offline Mishma

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Re: Innate Immune Response to HIV
« Reply #15 on: February 28, 2013, 03:37:13 PM »
It escaped my attention on the Zinc Finger Protease (nuclease) "stacking" posts that the gene cassette they use includes the innate pattern recognition receptors TRIM5 alpha, which recognizes the capsid of HIV within the cells cytoplasm and APOBEC3G, which interferes with viral replication. CCR5, which is edited out in this system, can also be considered an innate pattern recognition receptor (Yes it normally binds a chemokine but it's structure doesn't change over the course of the immune response) as well as one of the HIVs co-receptors required for entry. 



http://en.wikipedia.org/wiki/APOBEC3G
http://en.wikipedia.org/wiki/TRIM5alpha

http://www.amfar.org/Stopping-HIV-Using-a-Cocktail-of-Genes-Rather-than-Drugs/?msource=1302enews

Stopping HIV Using a Cocktail of Genes Rather than Drugs: An amfAR Grantee Update

By Jeffrey Laurence, M.D.
Published Friday, February 15, 2013


Dr. Matthew Porteus
 
The headline in The Huffington Post heralded this new amfAR-funded work by stating that, “HIV-resistant cells created by Stanford researchers could protect patients from AIDS.” An ABC News blog further declared that, “Genetically modified cells could prevent death from HIV/AIDS, study finds.” And what led to all this promise and excitement? amfAR grantees Dr. Matthew Porteus, working in the Department of Pediatrics at Stanford University, and Sara Sawyer at the University of Texas, have worked with colleagues to create, in the test tube, genetically modified human T cells resistant to HIV infection.

Porteus, Sawyer and colleagues took a lead from prior amfAR-funded research into so-called “restriction factors,” or normal cellular genes that have the capacity to limit the growth of HIV. Utilizing a novel and complex gene strategy based on enzymes that can cut into a host’s DNA, they were able to insert such factors—including APOBEC3G and TRIM5α—into a host gene, CCR5, disrupting that gene in the process. CCR5 normally codes for a critical receptor, or door, by which most strains of HIV enter a cell.

- See more at: http://www.amfar.org/Stopping-HIV-Using-a-Cocktail-of-Genes-Rather-than-Drugs/?msource=1302enews#sthash.W8D87keH.dpuf
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Mishma

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Innate Immune Response to HIV
« Reply #16 on: August 21, 2013, 08:03:30 PM »
I suspect everyone reading knows the "central dogma," of Molecular Biology, at least the simplist view we held onto until the 90's. DNA codes for RNA and RNA in turn is the blueprint for proteins, enzymes and other structural components that make us up. During the early 90's and continuing up till today we've become aware of what is called RNA interference, a process whereby a single strand of RNA is covered by it's complement and is therefore marked for degradation through a innate pattern/damage recognition receptor(s).

HIV is able to escape intracellular immune surveilance and integrates itself within our DNA, capturing along the way several important transcription factors which are involved in immune activation. Now we have long interferring RNA's, one of which is identified in this paper.

If you find this abstract too difficult I've given links further up this post that describe in detail the Innate Immune Responce.




http://www.sciencemag.org/content/341/6147/789.abstract?sid=33a13fed-1155-41aa-9d78-dbb398b3e9e2

Published Online August 1 2013
Science 16 August 2013:
Vol. 341 no. 6147 pp. 789-792
DOI: 10.1126/science.1240925
REPORT
A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response Genes
Susan Carpenter1,2, Daniel Aiello1, Maninjay K. Atianand1, Emiliano P. Ricci3, Pallavi Gandhi1, Lisa L. Hall4, Meg Byron4, Brian Monks1, Meabh Henry-Bezy1, Jeanne B. Lawrence4, Luke A. J. O’Neill2, Melissa J. Moore3, Daniel R. Caffrey1,*,†, Katherine A. Fitzgerald1,*,†
+ Author Affiliations

1Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
3Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
↵†Corresponding author. E-mail: kate.fitzgerald@umassmed.edu (K.A.F.); daniel.caffrey@umassmed.edu (D.R.C.)
↵* These authors contributed equally to this work.

ABSTRACTEDITOR'S SUMMARY
An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

 


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