Role of Adaptive vs. Innate Immune Activation in non-AIDS Morbidity Peter W. Hunt, MD Associate Professor of Medicine UCSF HIV/AIDS Division.
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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 • Monocyte activation and inflammation a target during treated HIV disease • Why this shift is occurring – Important caveats • Implications for future clinical trials 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 CD8+ T cell activation predicts survival better than VL in patients with AIDS (CD4<200) P=0.001 Janice Giorgi P=0.02 Survival Survival Giorgi, JID, 1999 (see also: Giorgi, JAIDS, 2002) T Cell Activation Declines with ART Hunt et al, JID, 2003; PLoS One, 2011 But Remains Abnormally High During ART-mediated Viral Suppresion Hunt et al, JID, 2003; PLoS One, 2011 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 Low CD4 Count during ART Predicts non-AIDS Death Young et al for COHERE cohort, PLoS Med, 2012 (see also Baker, AIDS, 2008) 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 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 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? What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia Innate Immune Activation (MØ/DC) ? Inflammation ? Coagulation ? T and B Cell Activation/ Dysfunction ? Non-AIDS Morbidity / Mortality What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia Innate Immune Activation (MØ/DC) ? Inflammation ? Coagulation ? T and B Cell Activation/ Dysfunction ? Non-AIDS Morbidity / Mortality High T Cell Activation Associated with Blunted CD4 Recovery during ART Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006) Inflammation and Innate Immune Activation are Increased in Patients with Poor CD4+ T cell Recovery on ART IL-6 CD4<350 CD4>500 sCD14 HIV- CD4<350 CD4>500 HIV- Lederman et al., JID, 2011 How do we get a better sense of the specific immunlogic pathways driving disease? 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) 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 Monocyte Activation Predicts Coronary Artery Calcium Progression: SUN Study T cell Activation Not Predictive Baker, CROI 2013, Abstract #66LB Do these markers predict clinical events? SMART: Inflammatory Markers Strongly Associated with Mortality and CVD Events Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) OR P-value OR P-value hs-CRP 3.1 0.02 1.6 0.20 IL-6 12.4 <0.0001 2.8 0.003 Amyloid A 3.1 0.05 1.6 0.12 Amyloid P 1.1 0.78 2.8 0.002 D-dimer 41.2 <0.0001 2.0 0.06 F1.2 1.3 0.64 0.8 0.56 Even after adjusting for CD4 count! Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009 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) Innate Markers Predict Mortality Independent of Nadir AND Current CD4 count Gut Epithelial Barrier Dysfunction IDO-1 Induction Monocyte Activation Inflammation / Coagulation Current CD4 count no longer predictive of mortality after adjusting for innate markers Also adjusted for current CD4 count Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790) Why does T cell “senescence” not predict mortality in HIV infection? A: Normal CD8+ T Cell Proliferation & Maturation CD57-, CD57+, ↑Telomere ↓Telomere Length Length Antigen B: CD28- Memory CD8+ Cells CD28+CD27+ Maturational/Proliferative Defect in HIV CD27-CCR7-RACD27+CCR7-RACD27-CCR7-RA+ CCR7+RACentral Memory Transitional Effector Memory TEMRA Inflammatory Cytokines Antigen IDO-1, PD-1+ Monocytes CD28+CD27+ CCR7+RACentral Memory CD28- Memory CD8+ Cells CD27+CCR7-RATransitional CD27-CCR7-RAEffector Memory CD27-CCR7-RA+ TEMRA Lee, CROI 2013, #294 A: Normal CD8+ T Cell Proliferation & Maturation CD57-, CD57+, ↑Telomere ↓Telomere Length Length Antigen B: CD28- Memory CD8+ Cells CD28+CD27+ Maturational/Proliferative Defect in HIV CD27-CCR7-RACD27+CCR7-RACD27-CCR7-RA+ CCR7+RACentral Memory Transitional Effector Memory TEMRA Inflammatory Cytokines Antigen IDO-1, PD-1+ Monocytes CD28+CD27+ CCR7+RACentral Memory CD28- Memory CD8+ Cells CD27+CCR7-RATransitional CD27-CCR7-RAEffector Memory CD27-CCR7-RA+ TEMRA Lee, CROI 2013, #294 HIV Disease Drives Expansion of CD28- CD8+ T Cells . . . % CD28of CD8+ T Cells % CD28of CD8+ T cells 100 P=0.0002 P=0.10 80 60 40 20 0 HIV- All CMV+ HIV+ ART+ VL<75 HIV+ ARTVL>10K Lee, CROI 2013, #309 But CD57 is inappropriately low on CD28- CD8+ T Cells in HIV infection % CD57+ of CD28-CD8+ T Cells % CD28of CD8+ T Cells % CD57+ of CD28-CD8+ T cells % CD28of CD8+ T cells 100 80 60 40 20 0 HIV- All CMV+ HIV+ ART+ VL<75 HIV+ ARTVL>10K P<0.0001 P=0.0003 100 80 60 40 20 0 HIV- HIV+ ART+ VL<75 HIV+ ARTVL>10K Lee, CROI 2013, #309 Low (Not High) CD57 on CD28- CD8+ T Cells Predicts Mortality in Treated HIV %CD57+ on CD28-CD8+ T Cells 4th Quartile 3rd Quartile 1.0 1.14 4.41 2nd Quartile 4.97 1st Quartile 0.1 1 10 100 Odds of Mortality (compared to 4th Quartile) *Subjects matched on age, gender, duration of viral suppression, presence of CMV retinitis, and nadir CD4+ cell count Lee, CROI 2013, #309 Higher Monocyte Activation Associated with the Low CD57 CD8+ T cell Defect % CD57+ of CD28- CD8+ T Cell SOCA 100 Spearman's rho: -0.24, P=0.002 80 60 Monocyte activation may cause T cell proliferative defects in HIV by: • PD1-driven IL-10 release 40 (Said, Nat Med, 2010) • IDO-1 induction 20 (Boasso, Blood, 2007) 0 900 1900 2900 3900 4900 sCD14 Level (ug/ml) Lee, CROI 2013, #309 What Specific Immunologic Pathways are Driving Disease during ART? CD4 Lymphopenia Innate Immune Activation (MØ/DC) ? Inflammation Non-AIDS Morbidity / Mortality Coagulation T and B Cell Activation/ Dysfunction ? Caveats… T / B Cell Activation Predicts NHL (MACS) Adjusted for age, duration HIV infection, and CD4 count Breen, Cancer Epi Bio, 2011 T Cell Activation may be an important contributor to HIV reservoir size… Hatano, JID, 2013 Implications for Clinical Trials 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 Lots of Within-subject Variability in IL-6 Std Dev of ∆ Wk 0-24: 0.38 log10pg/ml ~2.4-fold relative change Hunt, Blood, 2013 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 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? Acknowledgements 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 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 R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA