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Immune Activation, HIV Persistence, and the Cure

Immune Activation, HIV Persistence, and the Cure. Daniel C. Douek , MD, PhD Bethesda, Maryland. From DC Douek , MD, at Atlanta, GA: April 10, 2013, IAS-USA. . Causes Of Chronic Immune Activation. Raised cytokine and chemokine levels are a consequence of immune activation

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Immune Activation, HIV Persistence, and the Cure

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  1. Immune Activation, HIV Persistence, and the Cure Daniel C. Douek, MD, PhDBethesda, Maryland From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA.

  2. Causes Of Chronic Immune Activation • Raised cytokine and chemokine levels are a consequence of immune activation • HIV-induced activation of innate immune system (N. Bhardwaj) • When virus load decreases after acute phase, immune activation remains elevated • Virus load alone is a poor predictor of disease progression (Rodriguez JAMA 2006) • Measures of immune activation predict disease progression independent of viral load (Giorgi, Deeks...) • Elite controllers who progress have increased activated CD38+ T cells (Hunt JID 2008) • When virus load is suppressed with ART immune activation still persists and predicts progression • Increased antigen load, bacterial overgrowth, herpes viruses (S. Deeks, P. Hunt) • Translocation of proinflammatory mediators across mucosae

  3. Consequences of HIV Infection in GI Tract Loss of tight junctions Mucus CD4 T cell loss Microbial products Enterocyte apoptosis • HIV-Infected Gut • Massive loss of CD4 T cells • Enteropathy • 2-10x increased permeability • Translocation of microbial products • Systemic immune activation • Healthy Gut • Tight epithelial junctions, mucus • Anti-microbial peptides, Abs, cells • Majority of CD4 T cells in body • Cross-talk between microbes and epithelial cells and immune cells

  4. Tem Tcm immune deficiency gut poor pathogen control microbial translocation CD4 depletion enteropathy Immune deficiency ART HIV Tem CMV immune activation Tcm Tem ??? target cells low thymic output LT fibrosis T/B cell dysfunction non-AIDS morbidity and mortality inflammation tissue damage coagulopathy

  5. Ongoing HIV Replication During ART? Although complete inhibition of viral replication is unlikely to be curative, all cure strategies are based on first having achieved complete suppression • Evidence against ongoing HIV replication on ART • Increasing evidence in favor of ongoing replication • Evidence it is associated with immune activation • The source of the sample is key (blood vs tissues) • The assay used to measure virus is critical

  6. HIV-Specific Immunity and HIV Persistence Immune activation adversely affects HIV-specific T cell responses Immune activation adversely affects CD4 T cell immune reconstitution What is relationship between HIV-specific T cell immunity and the HIV reservoir?

  7. HIV-Specific Immunity and HIV Persistence CD8 CD4 r = - 0.56, P = 0.01 r = - 0.37, P = 0.12 Hatano JID 2011 On suppressive ART, strong HIV specific T cell responses in the gut mucosa are associated with lower levels of PBMC viral DNA

  8. poor immune control of HIV poor pathogen control microbial products target cell generation infected cell proliferation virus transcription virus production new infection events low thymic output lymphoid fibrosis poor CD4 T cell renewal T/B cell dysfunction mucosal damage immune activation HIV effects of HIV infection

  9. Chemokine receptor inhibitors: maraviroc, TB-652 Anti-infective therapy: CMV, EBV, HSV, HCV/HBV Microbial translocation: sevelamer, colostrum, rifaximin Enhance T cell renewal: Growth Hormone, IL-7 Anti-fibrotic drugs: pirfenidone, ACEi, ARBs, KGF Anti-aging: caloric restriction, sirtuin activators, vitamin D, omega-3 fatty acids, rapamycin, diet, exercise Therapeutic Interventions in Development • Anti-inflammatory drugs: • Chloroquine, HCQ • Minocycline • NSAIDs (COX-2i, aspirin) • Statins • Methotrexate • Thalidomide, lenalidomide, pentoxyfylline (weak TNF inhibitors) • Biologics (e.g., TNF inhibitors, IL-6 inhibitors, anti-IFNa, anti-PD1 • Anti-coagulants: • low dose warfarin, dabigatran, aspirin, clopidogrel Combination therapy may be necessary

  10. In The Context of The Cure • Multiple mechanisms account for HIV persistence, all of which are being addressed therapeutically • The unifying theme is to reduce HIV reservoir size • Reduce inflammation • Increase immune function • Early ART and ART intensification • Gene therapy to reduce reservoir size • Stem cell transplants can reduce reservoir size • Drugs with biologic activity against latent virus exist • Vaccines may enhance host-clearance mechanisms Combination therapy may be necessary

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