Immune Ageing and Viral Co-Factors Peter W. Hunt, MD Associate Professor of Medicine Division of Experimental Medicine, UCSF

Disclosures Consultant Merck Gilead Viiv

Potential Role of Inflammation in Driving Morbidity in Older HIV+ Individuals ART Toxicity Age- associated Morbidity Lifestyle Persistent Inflammation CMV HCV Deeks and Phillips, BMJ, 2009

CMV

10% of circulating memory T cell repertoire is CMV-specific! CMV elicits massive immune responses even in asymptomatic HIV- individuals 10% of circulating memory T cell repertoire is CMV-specific! Sylwester/Picker, JEM, 2005

CD8+ T Cell Proliferation & Maturation with CMV ↑Telomere Length CD57+, ↓Telomere Length “Senescence” phenotype associated with mortality in elderly Wikby, Exp Ger, 2002 Hadrup, JI, 2006 Antigen Lee, PLoS One, 2014 CD28- Memory CD8+ Cells CD28+CD27+ CCR7+RA- CD27+CCR7-RA- CD27-CCR7-RA- CD27-CCR7-RA+ Central Memory Transitional Effector Memory TEMRA

CMV does not impair (and may enhance) flu vaccine responses in young HIV- individuals Old CMV IgG- CMV IgG+ Furman/Davis, Science Transl Med, 2015

CMV Causes CD8 Expansion and Inflammation in HIV Infection CD8+ T Cell Counts IP-10 sTNF-RII D-Dimer CMV causes ↑CX3CR1 expression, trafficking of T cells/monos to vascular tissue CX3CR1+ CD8s also express PAR-1, which can activate coagulation cascade CMV viremia (or prior end organ dz) predicts venous thromboembolism in HIV Freeman, JID, 2014 (see also: Sacre, AIDS, 2011; Mudd, JID, 2016; Musselwhite, AIDS 2011)

in HIV+ Patients with CD4<350 despite ART Blocking Asymptomatic CMV Replication with Valganciclovir ↓ Immune Activation in HIV+ Patients with CD4<350 despite ART -4.4% HIV- Median Valacyclovir, which has strong anti-HSV1/2 but minimal anti-CMV activity, failed to decrease immune activation (Yi et al, CID, 2013). Hunt et al, JID, 2011

Cardiovascular Effects of CMV

Higher CMV-specific CD8 IFN-g Production Associated with More Atherosclerosis Hsue et al, AIDS, 2006 (see also: Parrinello, JID, 2012; Lo, AIDS, 2010)

CMV Sero-status Predicts Non-AIDS Events (and less so AIDS…): ICONA Cohort Strongest effect for CAD (HR 2.3) CMV replicates in vascular endothelium and appears to contribute to transplant vasculopathy (Valantine, Circ, 1999) Lichtner et al, JID, 2015 (see also Hsue, AIDS, 2006)

A role of CMV in other aspects of HIV pathogenesis?

CMV may plausibly drive clonal proliferation of HIV-infected cells Seminal CMV Shedding Associated with Higher PBMC HIV Reservoirs during ART CMV may plausibly drive clonal proliferation of HIV-infected cells Gianella, JV, 2014

CMV May Also Contribute to Microbial Translocation in HIV Infection Maidji, PLoS Path, 2017

Hepatitis C Virus

No increased risk of CAD or cancer HCV appeared to increase the risk of: T2DM Kidney disease Osteoporotic fractures Only T2DM risk declined with Rx (IFN-based) (see also editorial by Lo Re III, CID, 2017)

Comparable reductions in sCD163 (P≤0.0004 for both) Greater and More Rapid Reversal of Type I IFN Signaling with DAA vs IFN-based HCV Rx IFN-based SVR Baseline Week 4 Week 12 P=0.004 -19% -47% DAA-based SVR Baseline Week 4 Week 12 P<0.001 -73% -70% Comparable reductions in sCD163 (P≤0.0004 for both) Good: DAAs reduce biomarkers that predict morbidity Bad: DAAs may result in loss of HBV control Mascia, PLoS One, 2017 (also: Tenorio, JID, 2014; Knudsen, JID, 2016; Chen, Hepatology, 2017)

Early Increase in LDL Cholesterol during DAA Treatment of HCV Oxidized LDL also increases during DAA Tx (Biliotti, CROI 2017, #575) Restoration of health or increased CAD risk? IFNs may suppress LDL (Schectman, Arterio Thromb 1992) Townsend, ARHR, 2016 (see also Frias, CROI 2017, #573)

Reactive Hyperemia Index Inconsistent Effects of DAA-based HCV Tx on CAD Surrogate Markers in Treated HIV (n=20) Reactive Hyperemia Index by peripheral arterial tonometry D-dimer Level (ng/ml) Baseline Post-SVR Better Worse Baseline Post-SVR …but sICAM-1, sE-selectin, and sCD163 all declined (P<0.01) Chew, Int. Co-Morbidities Workshop, 2016

Summary CMV appears to increase immune activation in treated HIV and may plausibly contribute to: Cardiovascular, thromboembolic disease HIV reservoirs and microbial translocation Need an interventional study to assess these hypotheses HCV treatment with DAAs causes massive reversal of Type I interferons Impact on CAD surrogate markers is mixed Impact on extra-hepatic events still unclear

Acknowledgements Hunt and McCune Labs Core Immunology Lab UCSD Elizabeth Sinclair, Lorrie Epling Jeff Milush, Chris Baker SFGH Cardiology Priscilla Hsue UARTO Helen Byakwaga David Bangsberg Mark Siedner NIAID/VRC Jason Brenchley Danny Douek University of Sao Paulo Vivian Avelino-Silva Esper Kallas CWRU Michael Lederman Mike Freeman Hunt and McCune Labs Rachel Rutishauser Josh Vasquez Charline Bacchus-Souffan Louise Swainson Ma Somsouk Sulggi Lee Ivan Vujkovich-Cvijin Mike McCune SCOPE/OPTIONS/UCSF Steve Deeks Jeff Martin Hiroyu Hatano Rick Hecht Chris Pilcher Rebecca Hoh SCOPE and OPTIONS Teams UCSF Drug Studies Unit Yong Huang UCSD Sara Gianella Davey Smith UCLA Kara Chew R01AI110271, R56AI100765, 1R21AI087035, 1R21AI07877 DDCF CSDA Roche, Inc.