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

2. Slide 2 of 10 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 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. Slide 3 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. Consequences of HIV Infection in GI Tract 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 Mucus HIV-Infected Gut Massive loss of CD4 T cells Enteropathy 2-10x increased permeability Translocation of microbial products Systemic immune activation CD4 T cell loss Loss of tight junctions Enterocyte apoptosis Microbial products

4. Slide 4 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. Tcm Tem gut Tcm Tem low thymic output LT fibrosis T/B cell dysfunction inflammation tissue damage coagulopathy non-AIDS morbidity and mortality immune deficiency CMV ??? HIV CD4 depletion enteropathy ART immune activation

5. Slide 5 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. 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 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

6. Slide 6 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. 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. Slide 7 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. On suppressive ART, strong HIV specific T cell responses in the gut mucosa are associated with lower levels of PBMC viral DNA r = - 0.56, P = 0.01 CD4CD8 r = - 0.37, P = 0.12 Hatano JID 2011 HIV-Specific Immunity and HIV Persistence

8. Slide 8 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. immune activation low thymic output lymphoid fibrosis poor CD4 T cell renewal T/B cell dysfunction mucosal damage target cell generation infected cell proliferation virus transcription virus production new infection events

9. Slide 9 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. 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 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-IFN , anti-PD1 Anti-coagulants: -low dose warfarin, dabigatran, aspirin, clopidogrel Combination therapy may be necessary Therapeutic Interventions in Development

10. Slide 10 of 10 From DC Douek, MD, at Atlanta, GA: April 10, 2013, IAS-USA. 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 In The Context of The Cure Combination therapy may be necessary