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Innate Immune Response to HIV

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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.

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.

Another excellent article that put ALL viruses in context to our genome.

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

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.

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.

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.

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

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:
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.

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    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.

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.;6/263/ec45

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


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).


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