The pathogenesis of persistent HIV-associated inflammation

during long-term antiretroviral therapy

Steven G. DeeksProfessor 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+H

LAD

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)

Does residual replication during

HAART contribute to chronic inflammation?

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

PBORGV

0 4 8 12 16 20 240

10

20

30

Weeks

% C

D38

+HLA

-DR

+C

D8+

T c

ells

(blo

od)

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

Hatano, Hunt, Yukl and Wong (IAS 2011)

Microbial translocation

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 = 0.001Pl

asm

a LP

S (p

g/m

L)

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

Chronic CMV Infection

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-

spec

ific

IFN

- -pro

duci

ng 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

Loss of T cell regenerative capacity

and altered immunoregulatory

responses

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

Telomeres and Telomerase

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

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

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