The pathogenesis of persistent HIV-associated inflammation during long-term antiretroviral therapy Steven G. Deeks Professor of Medicine University of California, San Francisco

Untreated and to a lesser degree treated HIV infection is associated with increased frequency of “activated” (CD38+ HLA-DR+) T cells 2

Activated CD38+ HLA-DR+ T cells are rapidly turning over in untreated disease Srinivasula et al., Blood 2011

Pre-treatment activation “set-point” strongly predicts extent of activation during suppressive HAARART Hunt et al, CROI 2010, Poster #306, and submitted

UARTO: High CD8+ T aell activation at month 6 of HAART predicts mortality in Ugandans with VL<400 In Cox Proportional Hazards models, each 10% increase in the frequency of activated (%CD38+ HLA-DR+) CD8+ T cells was associated with an increased hazard of death even after adjustment for baseline CD4 count (HR: 1.62, P=0.048) or month 6 CD4 count (HR: 1.61, P=0.042). Hunt et al, CROI 2010, Poster #306, and submitted

Why are “activated” T cells elevated in antiretroviral-treated disease? Residual HIV replication CMV (and other prevalent co-infections) Microbial translocation Lack of immunoregutory responses Thymic dysfunction and residual defects in adaptive immune responses Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)

Does residual replication during HAART contribute to chronic inflammation? 7

Raltegravir intensification had no effect on CD8+ T cell activation (blood and GALT) suggesting that active viral replication is not a causes of persistent inflammation 30 20 % CD38+HLA-DR+ CD8+ T cells (blood) 10 PBO RGV 4 8 12 16 20 24 Weeks Hatano et al., JID 11

Massanella et al., CROI 2011

The size of HIV reservoir (as defined by RNA/DNA ratio) is associated with frequency of activated CD4+ T cells in rectal tissues The GALT RNA was quantified from the LTR (long/processive transcripts), and thus represents a sum of unspliced and spliced HIV RNA. Based on the PLUS study, very little of this RNA should be spliced. Hatano, Hunt, Yukl and Wong (IAS 2011)

Microbial translocation 11

Most (but not all) studies have shown that HIV infection results in mucosal damage, microbial translocation and inflammation; this effect persists during HAART Brenchley JM Nature Medicine 2006

Levels of sCD14 (a marker of LPS and/or monocyte/macrophage activation) predicts mortality in HIV disease independent of other factors (SMART study) Sandler JID 2011

Chronic CMV Infection 14

CMV elicits massive immune responses even in asymptomatic young HIV uninfected adults Sylwester/Picker, JEM, 2005

CMV-specific T cell responses are approximately five fold higher in treated HIV infected adults Naeger et al, PLoS ONE 2009

Higher CMV-specific CD8 IFN-γ production associated with atherosclerosis in several studies Hsue et al, AIDS, 2006

Loss of T cell regenerative capacity and altered immunoregulatory responses 18

HIV-associated inflammation → T reg response → TGF-β → Collagen deposition → Fibrosis → Reduced IL-7 → Reduced T cell regeneration → Inflammation CD3+ Collagen 1 + Desmin +

T Cell Proliferative Defect Inflammation increases IDO production which in turn causes Th17 depletion, microbial translocation and more inflammation T Cell Proliferative Defect ↓Tryptophan IDO Induction in DC/MØ IFN-γ LPS ↑HAA Th17 Depletion Microbial Translocation Favre/McCune Science Translationa Med 2010 Hunt et al, IAS, 2011, #MOAA0105

Telomeres and Telomerase 21

Telomerase (a reverse transcriptase) is inhibited by certain NRTIs (ZDV, d4T, TDF), and treated HIV disease is associated with shorter telomeres Strahl and Blackburn. Nuc Acid Res 1994:22:893–900 Leeansyah et al. 6th IAS on Pathogenesis, Clinical Research and Prevention, Rome, July 2011; Poster TUPE127

Annu Rev Med 2011;62:141-55.

Conclusions T cell activation as defined by CD38 and HLA-DR expression remains elevated during HAART Functional characteristics of cells not fully defined T cell activation associated with disease Multiple mechanisms cause activation during HAART Residual HIV replication (controversial) Microbial translocation (controversial) CMV and other co-pathogens (needs confirmation) Loss of T regulatory cells and other immunoregulatory responses Lymphoid fibrosis (may be central to preceding causes) Homeostatic proliferation (not “activation”) Telomerase inhibition (indirect effect) Metabolic syndrome, abdominal obesity

NIAID RO1 AI087145, K24AI069994, CNICS (5R24AI067039), CLIC Acknowledgements SCOPE Cohort / UCSF Peter Hunt Hiroyu Hatano Jeff Martin David Naeger Rebecca Hoh Rick Hecht Vivek Jain Elizabeth Sinclair Lorrie Epling Mike McCune Elsewhere Netanya Sander Danny Douek Michael Lederman Alan Landay Russell Tracy April Ferre Barbara Shacklett Tim Shacker Ashley Haase Larry Corey Robert Kaplan Sharon Lewin NIAID RO1 AI087145, K24AI069994, CNICS (5R24AI067039), CLIC