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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%
CD
38+
HL
AD
R+
CD
8+ T
Cel
ls
0
20
40
60
80
HIVNegative(n=82)
Non-Controller
(n=65)
HAART(n=132)
P < 0.001
P < 0.001
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
Hunt et al, CROI 2010, Poster #306, and submitted
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).
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)
Slide #8Raltegravir intensification had no effect on CD8+ T cell activation (blood and GALT) suggesting that
active viral replication is not a causes of persistent inflammation
PBO
RGV
0 4 8 12 16 20 240
10
20
30
Weeks
% C
D38
+H
LA
-DR
+C
D8+
T c
ells
(b
loo
d)
Hatano et al., JID 11
The size of HIV reservoir (as defined by RNA/DNA ratio) is associated with frequency of activated
CD4+ T cells in rectal tissues
Hatano, Hunt, Yukl and Wong (IAS 2011)
Most (but not all) studies have shown that HIV infection results in mucosal damage, microbial translocation and
inflammation; this effect persists during HAART
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001P
las
ma
LP
S (
pg
/mL
)
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
2.07-2.34
2.35-2.75
>2.75
<2.07x106 pg/ml
Univariate
Adjusted for IL-6, D-dimer, CRP, SAA and virus load
0 5 10 15 20 25
OR (95% CI)
sCD14: OR of Death by Quartile
Sylwester/Picker, JEM, 2005
CMV elicits massive immune responses even in asymptomatic young HIV uninfected adults
CMV-specific CD8 ResponsesBy HIVStatus
0
1
2
HIV-N=37
HIV+Untreated
N=102
HIV+HAART+
N=283
P<0.001
P<0.001
% p
p65-s
pecif
ic
IFN
- -p
rod
ucin
g C
D8+
T C
ells
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
HIV-associated inflammation → T reg response → TGF-β → Collagen deposition → Fibrosis → Reduced IL-7 → Reduced T cell regeneration → Inflammation
CD3+
Collagen 1 +
Desmin +
Inflammation increases IDO production which in turn causes Th17 depletion, microbial
translocation and more inflammation
IFN-γLPS
IDOInductionin DC/MØ
↓TryptophanT Cell
Proliferative Defect
MicrobialTranslocation
↑HAA Th17 Depletion
Favre/McCune Science Translationa Med 2010Hunt et al, IAS, 2011, #MOAA0105
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 1994:22:893–900Leeansyah et al. 6th IAS on Pathogenesis, Clinical Research and Prevention, Rome, July 2011; Poster TUPE127
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
AcknowledgementsElsewhereNetanya SanderDanny DouekMichael LedermanAlan LandayRussell TracyApril FerreBarbara ShacklettTim ShackerAshley HaaseLarry CoreyRobert KaplanSharon Lewin
SCOPE Cohort / UCSFPeter HuntHiroyu HatanoJeff Martin David NaegerRebecca HohRick HechtVivek JainElizabeth SinclairLorrie EplingMike McCune
NIAID RO1 AI087145,
K24AI069994, CNICS
(5R24AI067039), CLIC