1. Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division

2. Treating Immune Activation in HIV What have we learned from recent unsuccessful attempts? Mechanistic pathways of HIV pathogenesis inform therapeutic interventions. Highlight ongoing and recently reported studies of novel interventions. –Importance of studying ART-suppressed patients A way forward

3. What have we learned from recent unsuccessful attempts to decrease immune activation?

4. IL-2 Increases CD4 Counts in Treated Patients Abrams et al, NEJM, 2009 IL-2 also decreases HLA-DR and CD38 expression (Kovacs, NEJM, 1995)

5. However, IL-2 Had No Effect on AIDS/Death Abrams et al, NEJM, 2009 P=0.47 P=0.55

6. Why Didn’t IL-2 Work? IL-2 Preferential Expansion of Tregs Suppression of Healthy T Cell Responses Increased CD4 Count Good for Health Bad for Health

7. Maraviroc Intensification Increases CD8 Activation Compared to Placebo Hunt, CROI, 2011, Abstract 153LB

8. >2-fold Increase in Plasma CCR5 Ligand Levels During Maraviroc Intensification Due to prevention of ligand-receptor complex internalization by CCR5+ cells (Lin/Corbeau, AIDS, 2007; Nakata, Antiviral Threrapy, 2010) RANTES/MIP-1a may activate monocytes/macrophages and neutrophils via CCR1

9. What Have We Learned? Immune system is complicated! –Multiple parallel and competing pathways, feedback loops Primary effects assessed in vitro may fail to capture important competing secondary effects in vivo Need for carefully designed placebo-controlled trials, follow up studies to elucidate these mechanisms May need to improve more than surrogate inflammatory markers to advance to clinical endpoint trials (i.e., FMD, BMD, etc).

10. What specific mechanisms should we intervene upon?

11. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

12. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

13. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

14. Anti-LPS antibodies have no effect on CD4 recovery: CORAL HIV+ On cART CD4<350 cells/ul ∆CD4<50 past 12 months RaltegravirHIBC + placeboHIBC + Raltegravirplacebo + + HIBC= hyperimmune bovine colostrum Enriched in anti-LPS antibodies n=18 RESULTS No effect on CD4 recovery No effect on LPS, sCD14, T cell activation Bykawaga et al, J Infect Dis 2011 (in press) Slide courtesy of Sharon Lewin

15. Microbial Translocation: Cause or Consequence of Immune Activation in Treated HIV Infection? Observational studies linking MT to immune activation cannot prove causality –Causality can only be formally addressed in clinical trials DC/Macrophage activation can cause IDO induction, ↓Th17, and microbial translocation Ongoing/Planned studies assessing blocking microbial translocation directly –Rifaximin (ACTG) –Sevalamer (ACTG)

16. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

17. Chloroquine Might Reduce CD8 Activation in Untreated HIV+ Patients ChloroquinePlacebo Murray, JV, 2010 No apparent effect on plasma HIV RNA Levels (though some missing data) Possible early decrease in plasma LPS Probable mechanism: TLR inhibition (3,4,7,8,9)

18. Hydroxychloroquine Did Not Reduce CD8 Activation in Untreated HIV+ Patients %CD38+HLA-DR+ CD8s Paton, IAS 2011, MOPE269 Why did viral load increase with HCQ? And why didn’t CD8 activation increase with the increase in VL? Viral Load Plasma HIV RNA Level (log 10 copies/ml)

19. Impact of Innate Immune Response Untreated HIV Disease The Bad: Immune Activation ↑ The Good: HIV replication ↓ Direct Antiviral Effects Adjuvant to HIV-specific T cells IL-6, TNFα↑ TF expression, D-dimer ↑ T cell turnover/exhaustion ↑ LN fibrosis ↑ Immune Activation ↓

20. Impact of Innate Immune Response During ART-mediated VL Suppression The Good: None VL already suppressed by drugs Antiviral Effects Irrelevant The Bad Immune Activation ↑ IL-6, TNFα↑ TF expression, D-dimer ↑ T cell turnover/exhaustion LN fibrosis

21. HCQ Decreases Immune Activation in ART- suppressed Immunologic Non-responders %CD38+ Memory CD8s Piconi, Blood, 2011 %CD69+ CD14+ Monocytes

22. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

23. Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation in HIV+ Patients with CD4<350 despite ART -4.4% HIV- Median Hunt et al, JID, 2011 Cytopenias may limit long-term usefulness. Need new, safer CMV agents!

24. Adapted from Appay V, et al. J Pathol. 2008;214:231-241. HIV-1 Infection Immunodeficiency Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion Malignancy, Infections Cytokine Secretion (eg, IL-6, TNFL) “Inflam-Aging” (eg, atherosclerosis, osteoporosis) HIV-Mediated Immune Activation and Aging TLR 7,8 Nef, gp120 Increased TF Expression and clotting CAD/Stroke, Thrombosis

25. Atorvostatin Decreases T Cell Activation in Untreated HIV Infection Atorvostatin 80mg Placebo Ganesan, J Infect Dis, 2011 24 untreated patients, X-over design Significant reduction in HLA-DR on CD8s during atorvostatin Tx No effect on plasma HIV RNA levels Studies ongoing in ART-suppressed patients

26. COX-2 Inhibition Decreases T Cell Activation in Untreated HIV Infection 27 untreated patients, 12 weeks celecoxib vs. placebo. Significant reduction in CD38 on CD8s during celecoxib Tx No effect on plasma HIV RNA levels CAD toxicity a potential problem with celecoxib ASA? Mesalamine? CD38 Molecules/cell Pettersen, JV, 2011 Celecoxib Placebo

27. Other Strategies to block Monocyte/Macrophage Activation? Combined CCR5/CCR2 blockade? –CCR5 inhibition increased immune activation, likely indirectly through MØ activation –CCR2 (MCP-1 receptor) blockade might overcome this effect? IDO inhibitors? –Prevent proliferative defects and allow for restoration of Th17 cells –Might interrupt vicious circle of microbial translocation and innate immune activation

28. Immunosuppressive Therapies Suppression of Healthy Immune Reponses Decreased Immune Activation The Good The Bad TNFα inhibitorsIL-6 inhibitors CTLA-4 analogsIL-23/IL-12 inhibitors SteroidsCyclosporine Methotrexate

29. A Way Forward… Target proximal causes of monocyte activation Small pilot trials to establish proof of principal –“Immunologic Non-Responders” have higher immune activation and are at highest risk for disease –Studying treated patients allows cleaner biologic inferences –Need to thoroughly evaluate mechanistic pathways in vivo Advance promising agents to mid-range trials with surrogate markers of end-organ disease –Liver, renal, bone (BMD), cardiovascular (FMD) Advance promising/safe/scalable interventions to clinical endpoint trials