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Role of Adaptive vs. Innate Immune Activation in non-AIDS Morbidity

Role of Adaptive vs. Innate Immune Activation in non-AIDS Morbidity. Peter W. Hunt, MD Associate Professor of Medicine UCSF HIV/AIDS Division. A shift in focus…. T cell activation as a target for interventions in the pre-ART era

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Role of Adaptive vs. Innate Immune Activation in non-AIDS Morbidity

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  1. Role of Adaptive vs. Innate Immune Activation innon-AIDS Morbidity Peter W. Hunt, MD Associate Professor of Medicine UCSF HIV/AIDS Division

  2. A shift in focus… • T cell activation as a target for interventions in the pre-ART era • Monocyte activation and inflammation a target during treated HIV disease • Why this shift is occurring • Important caveats • Implications for future clinical trials

  3. Dec 10, 1981 Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon Leu3=CD4 T10=CD38

  4. CD8+ T cell activation predicts survival better than VLin patients with AIDS (CD4<200) P=0.001 Janice Giorgi P=0.02 Survival Survival Giorgi, JID, 1999 (see also: Giorgi, JAIDS, 2002)

  5. T Cell Activation Declines with ART Hunt et al, JID, 2003; PLoS One, 2011

  6. But Remains Abnormally High During ART-mediated Viral Suppresion Hunt et al, JID, 2003; PLoS One, 2011

  7. Is T cell activation a cause of disease in treated HIV infection or simply a marker for some other process? Important for identifying targets for novel interventions

  8. Low CD4 Count during ART Predicts non-AIDS Death Young et al for COHERE cohort, PLoS Med, 2012 (see also Baker, AIDS, 2008)

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

  10. However, IL-2 Had No Effect on AIDS/Death P=0.47 CD4 count (and CD38 / DR expression) is not 100% specific for the pathophysiologic pathway mediating disease. P=0.55 Abrams et al, NEJM, 2009

  11. Why didn’t IL-2 work? • May have expanded the wrong type of CD4+ T cells (regulatory cells). • Impaired functional immune responses? • Could CD4+ T cell count just be a marker for some other immunologic process?

  12. What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia ? Non-AIDS Morbidity / Mortality Inflammation ? Innate Immune Activation (MØ/DC) Coagulation ? T and B Cell Activation/ Dysfunction ?

  13. What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia X ? Non-AIDS Morbidity / Mortality Inflammation ? Innate Immune Activation (MØ/DC) Coagulation ? T and B Cell Activation/ Dysfunction ?

  14. High T Cell Activation Associated with Blunted CD4 Recovery during ART Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)

  15. Inflammation and Innate Immune Activation are Increased in Patients with Poor CD4+ T cell Recovery on ART IL-6 sCD14 HIV- HIV- CD4>500 CD4>500 CD4<350 CD4<350 Lederman et al., JID, 2011

  16. How do we get a better sense of the specific immunlogic pathways driving disease?

  17. Abnormal CSF Neopterin Levels Persist Despite 4 Years of VL Suppression 60% Abnormal Eden et al., JID , 2007 (see also: Burdo, AIDS, 2013; Lyons, JAIDS, 2011; Letendre, CROI 2012, Abstract #82)

  18. CD8+ T Cell Activation is Not Persistently Elevated in CSF During Suppressive ART T cell activation in the CNS is unlikely to explain persistent neurocognitive dysfunction in ART-suppressed individuals Sinclair, JAIDS, 2008

  19. Monocyte Activation Predicts Coronary Artery Calcium Progression: SUN Study T cell Activation Not Predictive Baker, CROI 2013, Abstract #66LB

  20. Do these markers predict clinical events?

  21. SMART: Inflammatory Markers Strongly Associated with Mortality and CVD Events Even after adjusting for CD4 count! Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009

  22. Innate Immune Activation Predicts Mortality More Strongly than T Cell Activation: SOCA Gut Epithelial Barrier Dysfunction IDO-1 Induction Monocyte Activation Inflammation / Coagulation Matched for age, gender, duration VL suppression, CMV retinitis, nadir CD4 Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)

  23. Innate Markers Predict Mortality Independent of Nadir AND Current CD4 count Gut Epithelial Barrier Dysfunction IDO-1 Induction Also adjusted for current CD4 count Monocyte Activation Inflammation / Coagulation Current CD4 count no longer predictive of mortality after adjusting for innate markers Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)

  24. Why does T cell “senescence” not predict mortality in HIV infection?

  25. Lee, CROI 2013, #294

  26. Lee, CROI 2013, #294

  27. HIV Disease Drives Expansionof CD28- CD8+ T Cells . . . P=0.0002 P=0.10 Lee, CROI 2013, #309 All CMV+

  28. But CD57 is inappropriately low onCD28- CD8+ T Cells in HIV infection P<0.0001 P=0.0003 Lee, CROI 2013, #309 All CMV+

  29. Low (Not High) CD57on CD28- CD8+ T Cells Predicts Mortality in Treated HIV *Subjects matched on age, gender, duration of viral suppression, presence of CMV retinitis, and nadir CD4+ cell count Lee, CROI 2013, #309

  30. Higher Monocyte Activation Associated with the Low CD57 CD8+ T cell Defect • Monocyte activation may cause T cell proliferative defects in HIV by: • PD1-driven IL-10 release (Said, Nat Med, 2010) • IDO-1 induction (Boasso, Blood, 2007) Lee, CROI 2013, #309

  31. What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia ? Non-AIDS Morbidity / Mortality Inflammation Innate Immune Activation (MØ/DC) Coagulation T and B Cell Activation/ Dysfunction ?

  32. Caveats…

  33. T / B Cell Activation Predicts NHL (MACS) Adjusted for age, duration HIV infection, and CD4 count Breen, Cancer Epi Bio, 2011

  34. T Cell Activation may be an important contributor to HIV reservoir size… Hatano, JID, 2013

  35. Implications for Clinical Trials

  36. CD8 Activation is a Reproducible and Responsive Marker Placebo Arm Std Dev of ∆ Wk 0-24: 0.13 log10% ~35% relative change Hunt, Blood, 2013

  37. Lots of Within-subject Variability in IL-6 StdDev of ∆ Wk 0-24: 0.38 log10pg/ml ~2.4-fold relative change Hunt, Blood, 2013

  38. sCD14 is much better, comparable variability to T cell activation Std Dev of ∆ Wk 0-24: 0.11 log10ug/ml ~29% relative change Hunt, Blood, 2013

  39. Summary • Several immunologic defects predict disease in treated HIV infection: • Innate immune activation and inflammation • CD4 lymphopenia • T cell / B bell activation and dysfunction • Innate immune activation and inflammation independently predict disease, less consistent for other markers. • Interventions designed to decrease activation of myeloid lineage cells may hold promise. • Statins, ASA? • Microbial Translocation interventions • Treating co-infections?

  40. Acknowledgements NIAID Jason Brenchley Danny Douek Irini Sereti Core Immunology Lab/DEM Elizabeth Sinclair Lorrie Epling Mike McCune SOCA Curtis Meinert Mark Van Natta ACTG Heather Ribaudo SCOPE/OPTIONS/UCSF Sulggi Lee Steve Deeks Jeff Martin Hiroyu Hatano Vivek Jain Rebecca Hoh Rick Hecht CWRU Wei Jiang Michael Lederman Nick Funderburg Brian Claggett U Minnesota Jason Baker R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA

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