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Immune-Based Interventions for HIV Infection and AIDS

Immune-Based Interventions for HIV Infection and AIDS. Alan Landay, PhD Professor and Chairman Department of Immunology/Microbiology Rush University Medical Center Chicago, Illinois. Immune Based Therapy 1981-2011 . Early years (1985-1995) mono and dual lead to suboptimal immune restoration

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Immune-Based Interventions for HIV Infection and AIDS

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  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 Therapy1981-2011 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 Need for strategies that target immune deficiency and immune activation 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

  4. HIV The Immune System and HAART Immunodeficiency OI/AIDS Restore CD4T Cell Number & function HIV Replication in CD4 cells HAART Reduce CD4 & CD8 T Cell activation Not normalized Immune Activation Inflammation 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/µl) and ESPRIT(CD4 >300 cells/µl) 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 10µg/kg, n=7 P=0.004, CYT107 20 µg/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. TLR-mediated immune activation in HIV blood 8 JANUARY 2009 I VOLUME 113, NUMBER 2:269

  15. Good IFN- a turns bad

  16. No Chloroquine 100 µM Chloroquine Chloroquine abrogates IFN-a production in vitro 3500 3000 2500 IFN-a pg/ml 2000 1500 1000 500 0 Media CpG-B CpG A TLR 7/8 HIV-Ada HIV-MN Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881

  17. No Chloroquine Chloroquine p=0.0020 p=0.0051 9.5 700 9.0 p=0.0197 p=0.0176 8.5 600 8.0 7.5 7.0 500 6.5 6.0 CD38 MFI CD8 Tcells 5.5 400 5.0 %CD38+HLA DR+ of CD8 Tcells 4.5 4.0 300 3.5 3.0 200 2.5 2.0 1.5 Media Media AT2-Ada AT2-Ada AT2-MN AT2-MN MV-R5 MV-R5 MV-X4 MV-X4 100 1.0 0.5 0.0 0 Chloroquine downmodulates both % and per cell expression of activation markers CD38 +HLADR+ cells in CD8+ T cells Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881

  18. SMART: Inflammatory Markers Strongly Associated With Mortality and CVD Events Kuller LH, et al. PLoS Med. 2008 ;5: e203. doi:10.1371/journal.pmed.0050203.

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

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

  21. Hope for the future: Targeting Immune-deficiency Immune-restoration & Immune-activation Chloroquine/Rifaxamin/Sevalamer?Statin + HAART IL-7+HAART CD4 Responders Immune-activation Relative values CD4 Non-Responders Viral Load Therapeutic vaccine (?) Diagnosis Time on HAART in years 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

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