1. Immune-Based Interventions for HIV Infection and AIDS Alan Landay, PhD Professor and Chairman Department of Immunology/Microbiology Rush University Medical Center Chicago, Illinois

2. Immune Based Therapy 1981-2011  Early years (1985-1995) mono and dual lead to suboptimal immune restoration  HAART (1995) reduced morbidity and mortality with sustained viral suppression and CD4 T cell increase and evidence of functional immune reconstitution  Post HAART (2000) cytokines and therapeutic vaccines were proposed to restore immunity  The SMART Study (2006) demonstrated the importance of immune activation/inflammation to non HIV co-morbidities and a focus on therapeutic agents to block inflammatory pathways

3. Impact of HAART on Immune System Restoration of CD4 T cell number and function based on nadir CD4 count however 5-30% of subjects did not demonstrate increase in CD4 T cell numbers Reduction of CD8 T cell activation but level isn't normalized despite viral control Some improvement in APC function but not full reconstitution to level of HIV negative control Need for strategies that target immune deficiency and immune activation

4. HIV The Immune System and HAART HIV Replication in CD4 cells Immunodeficiency OI/AIDS Immune Activation Inflammation HAART Restore CD4T Cell Number & function Reduce CD4 & CD8 T Cell activation Not normalized CVD Bone Renal Neurocog & Cancers

5. Therapies for Restoring Immunodeficiency Cytokines IL2, IL7, IL12, GM-CSF Therapeutic Vaccines

6. IL2 Phase III Studies SILCAAT(CD4 50-300 cells/ µ l) and ESPRIT(CD4 >300 cells/ µ l) Median CD4+ Cell Counts during the Study Period, according to Study and Treatment Group N Engl J Med 2009;361:1548-59

7. However No clinical Benefit of IL2 on OI or Death More Grade 4 Events in ESPRIT (many thrombotic) CD4 T cells that increased were T regulatory cells(CD25+FOXP3+) that may have contributed to clinical progression (Levy et al PNAS 2010) IL2 increases inflammatory markers(hsCRP and D Dimer) that impact non infectious complications(Porter et al AIDS 2009)

8. Immune deficiency: Is IL 7 an answer???  Good toxicity profile and active at low doses  Expansion of both naïve and central memory CD4 and CD8 T cells and not T-regs  Minimal T cell activation during cycle

9. Changes in CD4 and CD8 T cells * Wilcoxon test P =0.006, CYT107 10 µ g/kg, n=7 P=0.004, CYT107 20 µ g/kg, n=8 P = 0.008 CYT107 30 µg/Kg, n=6 Placebo, n=6 CYT107 treatment increases T cell number in a dose dependent manner Levy Y, ICAAC 2009

10. Therapeutic Vaccines Where we want to go Need to induce durable T cell response Need to optimize CD8 T cell response Need to enhance innate immune response, i.e. DC and NK Control of HIV replication following therapeutic interruption Where are we No Therapeutic Immunization strategy has produced robust HIV Control following Analytic Treatment Interruption Role of neutralizing antibody not clear

11. Why Haven’t We Succeded Haven't found appropriate immunogen Lack of enhancement of APC function Induction of regulatory cells(Tregs or MSDC) that blunt T cell responses Persistence of immune dysfunctional molecules on CD4 and CD8 effectors(PD1, CTLA-4)

12. Immune Activation Inflammation

13. What’s Driving Immune Activation During Treated HIV Infection? Low-level HIV replication or release? HIV Driven Interferon Alpha Production? Microbial Translocation? Co-Infections (CMV or HCV)? Homeostatic Proliferation?

14. blood 8 JANUARY 2009 I VOLUME 113, NUMBER 2:269 TLR-mediated immune activation in HIV

15. Good IFN- a turns bad

16. 0 500 1000 1500 2000 2500 3000 3500 MediaCpG-BCpG ATLR 7/8HIV-AdaHIV-MN No Chloroquine 100 µM Chloroquine IFN-  pg/ml Chloroquine abrogates IFN-  production in vitro Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881

17. Chloroquine downmodulates both % and per cell expression of activation markers CD38 +HLADR+ cells in CD8+ T cells No Chloroquine Chloroquine Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881

18. SMART: Inflammatory Markers Strongly Associated With Mortality and CVD Events Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) ORP-valueORP-value hs-CRP3.50.0041.60.20 IL-612.6<0.00012.80.003 Amyloid A2.30.081.60.12 Amyloid P1.10.902.80.002 D-dimer13.3<0.00012.00.06 F1.21.40.450.80.56 Kuller LH, et al. PLoS Med. 2008 ;5: e203. doi:10.1371/journal.pmed.0050203.

19. HIV Causes Disruption of the Gastrointestinal Tract HIV- HIV+ Loss of CD4+ T cells Enterocyte apoptosis Loss of tight junctions Microbial translocation Brenchley & Douek, Mucosal Immunol, 2008 Gut lumen Lipopolysaccharide Intestinal fatty acid binding protein (I-FABP) Gut parenchyma

20. Approaches to Block Activation/inflammation & Microbial Translocation  Chloroquine : Activation inhibitor  Statins/anti-IL-6: Inflammation inhibitors  Rifaxamin/Sevalamer: MT inhibitors

21. Immune-activation CD4 Responders CD4 Non-Responders Viral Load Relative values DiagnosisTime on HAART in years Chloroquine/Rifaxamin/Sevalamer ?Statin + HAART IL-7+HAART Therapeutic vaccine (?) Hope for the future: Targeting Immune-deficiency Immune-restoration & Immune-activation Desai S, adaptation : “Treatment Paradigms in HIV disease” From Marie-Lise Gougeon Nature Reviews Immunology, 2003; Sereti I Blood 2009, Catalfamo M, JI 2011, Dinoso JB, PNAS,2009

22. Rush Seema Desai Jeff Martinson NIAID Irini Sereti Larry Fox Netanya Sandler Case Michael Lederman