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Inflammation/Viral Replication/HIV Persistence....Reservoirs....Anti-Inflammation HIV Cure Strategies....VX-765, a small-molecule inhibitor of caspase-1, a potential anti-inflammatory drug/Cure Strategy to reduce reservoir?????......IP-10.... anti-inflammatory/HIV Cure strategy
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From Jules: controlling inflammation may improve chance for cure....limiting size of reservoirs & increase ability to flush out or deplete reservoirs.
How HIV Destroys Immune Cells, Blocking HIV Cell Death with Vertex Drug- 2 new studies. Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS
http://www.natap.org/2013/HIV/122713_02.htm
"A key protein involved in pyroptosis is caspase 1, and an experimental caspase-1 inhibitor made by Vertex Pharmaceuticals in Cambridge, Massachusetts, had already been tested in humans as a potential treatment for epilepsy. The drug, VX-765, failed to help epileptics, but six-week-long studies suggested that it was safe."
Inflammation as an Obstacle for Remission: Lessons Learned From Non-Human Primate Models
Michaela Muller-Trutwin
Institut Pasteur, Paris, France
CROI webcast:
http://www.croiwebcasts.org/console/player/22120?mediaType=slideVideo&
Background: Chronic immune activation (IA) during HIV-1 infection persists even in patients with controlled viremia. This residual inflammation might fuel
viral replication by creating new target cells and thus could represent an additional obstacle for cure. Early treatment likely has a favourable impact on the
reduction of viral reservoirs, and eventually on the inflammatory set point. Non-human primate models allow analyzing the early events after viral infection,
exploring the nature of the viral reservoirs in tissues and searching the factors, which initiate chronic immune activation. Several non-human primate
models for virological or inflammatory control exist. We have shown previously that natural hosts of SIV (African green monkeys, AGM) are capable to
efficiently resolve inflammation by the end of acute SIVagm infection. Based on this observation in AGMs, we had analyzed if the early level of inflammation
during HIV-1 infection would predict the disease progression rate. We reported elevated plasma CXCL10/IP-10 levels during primary HIV-1 infection being
more robust predictors of rapid progression toward AIDS than viral RNA and CD4 counts.
Conclusions: Here, we show that during acute HIV-1 infection, plasma IP-10 level was a better predictor of rapid disease progression than viral DNA.
Moreover, we evaluated whether the plasma levels of IP-10 already before SIV infection and before HIV-1 infection (Amsterdam Cohort Studies) have an
impact on the outcome of infection. We quantified the expression of an endogenous antagonist of IP-10 and observed that it's frequency is decreased during primary HIV-1 infection in those patients who rapidly loose their CD4+ T cells (ANRS PRIMO Cohort No6)...."higher risk of rapid progression towards AIDS in patients with higher IP10 levels before HIV-infection....found a correlation of plasma IP10 & HIV DNA levels in PBMS in acute infection & 12 months later....suggests a link of IP-10 & viral reservoirs") . Finally, we investigated the source of IP-10 in Humans and in non-human primates (rhesus macaques and African green monkeys), probing blood and relevant tissues, notably the gut (in the simian models). The IP-10 expression in intestinal CD4+ cells was associated with IP-10 plasma levels, suggesting that plasma levels can reflect the levels of IP-10 production in the gut and/or that these gut cells represent the major source of systemic IP-10. These studies are in favor of IP-10 as a robust early biomarker for inflammation ("and for viral reservoir....IL21 treatment ....reduced IP10 & sCD14") and of efforts combining viral suppressive therapies with anti-inflammatory strategies.
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Pyroptosis Drives Both CD4 T Cell Death and Chronic Inflammation in HIV-Infected Lymphoid Tissues
Gilad Doitsh1, Nicole Galloway1, Xin Geng1, Kathryn Monroe1, Zhiyuan Yang1, Orlando Zepeda2, Peter Hunt2, Hiroyu Hatano2, Stefanie Sowinski1, Warner C. Greene1
1Gladstone Institute of Virology and Immunology, San Francisco, CA, United States, 2University of California, San Francisco, San Francisco, CA, United States
[CROI webcast: http://www.croiwebcasts.org/console/player/22153?mediaType=slideVideo&]
Background: The progressive loss of CD4 T cells in HIV-infected individuals is the over-arching cause of AIDS. Apoptosis is the mechanism by which
productively infected CD4 T-cells die. In contrast, very little is known about how "bystander" resting CD4 T cells die in lymphoid tissues. These cells are
refractory to productive HIV infection yet they account >95% of the CD4 T cell losses occurring in many lymphoid tissues like tonsil and spleen.
Methodology: Human lymphoid aggregated cultures (HLACs) were prepared using tonsil and spleen tissue; lymph nodes from consenting HIV-infected
volunteers not on antiretroviral therapy were surgically excised and used in immuno-histological staining studies.
Results: Our finding demonstrate that productive HIV infection in activated CD4 T cells from tonsil and spleen (95%) leads to by caspase-1-mediated
pyroptosis, an intensely inflammatory form of programmed cell death. In the pyroptotic death pathway, cytoplasmic contents and pro-inflammatory
cytokines including IL-1ß, are released into the extracellular space. Surprisingly, lymphoid CD4 T-cells, but not CD8 T cells or B cells in the same tissue,
are primed to mount proinflammatory death responses as reflected by high-level expression of pro-IL-1beta. These events combine to create a vicious
pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to become abortively infected and die by pyroptosis causing
more inflammation. Cell-to-cell transmission of HIV is obligately required to elicit this pyroptotic death response-cell free virions are ineffective Pyroptosis
is efficiently blocked by VX-765, a small-molecule inhibitor of caspase-1 that has been shown to be safe in humans. Analysis of lymph nodes from HIV-infected subjects confirms caspase-1 dependent pyroptotic death of bystander CD4 T cells and release of IL-1beta.
Conclusions:
1. CD4 T-cell death in HIV-infected lymphoid tissues is principally controlled by caspase-1-mediated pyroptosis, an intensely inflammatory form of programmed cell death.
2. Pyroptosis provides a new and exciting nexus between CD4 T-cell death and inflammation with strong implications for HIV pathogenesis and disease progression.
3. Small-molecule inhibitors of caspase-1 could form a promising new "anti-AIDS" therapy that complements current treatment strategies by altering the detrimental host innate immune response to the virus rather than the virus itself.
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