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

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

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

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

5. 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

6. 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)

7. Does residual replication during HAART contribute to chronic inflammation?7

8. 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

9. Massanella et al., CROI 2011

10. 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)

11. Microbial translocation11

12. 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

13. 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

14. Chronic CMV Infection 14

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

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

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

18. Loss of T cell regenerative capacity and altered immunoregulatory responses18

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

20. 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

21. Telomeres and Telomerase21

22. 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

23. Annu Rev Med 2011;62:

24. 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

25. 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