the clinical implications of hivthe clinical implications...
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The clinical implications of HIVThe clinical implications of HIV persistence during therapy
St G D kSteven G. DeeksProfessor of Medicine
University of California, San Francisco
T cell activation declines during long-term HAART but remains abnormal even after manyHAART, but remains abnormal, even after many years of viral suppression
R+
60
80P < 0.001
P < 0.00138
+HLA
DR
8+ T
Cel
ls
40
60
% C
D3
CD
8
0
20
0HIV
Negative(n=82)
Non-Controller
(n=65)
HAART(n=132)
Hunt PW, et al. J Infect Dis. 2003;187:1534-1543 and unpublished
Many Age-associated Diseases Are More Common in Treated HIV Disease Than InCommon in Treated HIV Disease Than In
Age-matched Uninfected Persons• Cardiovascular disease• Cancer (non-AIDS)
Multiple• Bone fractures/osteopenia• Left ventricular dysfunction
Multiple factors likely explain this increased risky
• Liver failure• Kidney failure
increased risk, including co-morbid conditions andKidney failure
• Cognitive decline• Frailty
conditions and antiretroviral drug toxicity
• Frailty• Immune system
Untreated and to a lesser degree treated HIV infection is i d i h i d i fl i hil h l l fassociated with increased inflammation, while the level of
inflammation during treatment predicts risk of disease
100
60
80
mat
ion
dise
ase
20
40
Infla
mm
Risk
of d
HIV Negative Untreated HAART0
Inflammation
Most (> 80%) patients on effective HAART have persistent low level viremiahave persistent low level viremia
ile 80
100
erc
en
ti
60
P Nelfinavir
20
40 Lopinavir/Ritonavir
2.50
20
-0.5 0 0.5 1 1.5 2
Median 3.1 copies RNA/mL at week 60
Plasma HIV RNA (log)2.50.5 0 0.5 1 1.5 2
Maldarelli, Palmer, et al. PLoS Pathogens 2007
Questions• Does HIV persistence predict and
possibly cause inflammation (or T cellpossibly cause inflammation (or T cell activation) and non-AIDS morbidity?
• Does inflammation contribute to HIV persistence?
• Can therapeutic interventions aimed at reducing inflammation (broadly defined)reducing inflammation (broadly defined) accelerate the decline in the size of the reservoir and hence contribute to areservoir and hence contribute to a cure?
Does residual HIVDoes residual HIVDoes residual HIV replication cause inflammation and
Does residual HIV replication cause inflammation andinflammation and perhaps non-AID inflammation and perhaps non-AID
morbidity?morbidity?
Clin Immunol 2008;126:315-21.
Raltegravir Intensification:Study DesignStudy Design
R lt i ( 15)
Randomized (n=30)
+ Raltegravir (n=15)400mg BID24 weeks
• VL < 40 copies/mL on HAART for 1 year
• CD4 < 350 for 1 year + Placebo (n=15)PBO BIDPBO BID24 weeksBloodGALT
(n=21)
-2 0 4 8 12 16 20 24
Weeks
Slide #10
Raltegravir Intensification Had No Effect on C ll i d RNA P i l DNA (Bl d)Cell-associated RNA or Proviral DNA (Blood)
3
RN
A)
Cell-associated RNA3
Proviral DNA
2
ssoc
iate
d R
mil
PBM
C)
2
ovir
al D
NA
il PB
MC
)
p = 0.600
1
og10
Cel
l-as
(S/C
o pe
r
0
1
log 1
0 Pr
o(p
er m
i
p = 0.99
0 4 8 12 16 20 24Weeks
lo
0 4 8 12 16 20 24Weeks
PBORGV
Slide #12Raltegravir intensification had no effect on CD8+ T cell activation (blood and GALT) suggesting that ce act at o (b ood a d G ) suggest g t at
active viral replication is not a causes of persistent inflammation
30R+ od
)
20HLA
-DR
lls (b
lo
PBO10C
D38
+H8+
T c
e
PBORGV
0
% C
CD
8
0 4 8 12 16 20 24Weeks Hatano et al., JID 11
Massanella et al., CROI 2011
Does inflammationDoes inflammationDoes inflammation and/or T cell activation
contribute to viral
Does inflammation and/or T cell activation
contribute to viralcontribute to viral persistence?
contribute to viral persistence?
The vicious circle of HIV-associated inflammation and HIV persistencep
Microcrobial translocation and HIV causes activate PDC l di t i dPDCs leading to increased IDO, reduced tryptophan levels, a shift in Th17/Tregratios and eventually moreratios and eventually more microbial translocation (“vicious circle”’)
This process is not fully eliminated by HAART
End result: ongoing T cell activation, homeostatic proliferation and lower HIV-specific T cell responses
Favre STM 2010Murray STM 2010
The size of HIV reservoir (as defined by RNA/DNA ratio) is associated with frequency of activatedratio) is associated with frequency of activated
CD4+ T cells in rectal tissues
Hunt, Yukl and Wong
The Size of HIV Reservoir is Predicted by the Level of Activated CD8+ T cells (in Sigmoid Colon)Level of Activated CD8+ T cells (in Sigmoid Colon)
During HAART, there is a higher frequency of HIV DNA in activatedDuring HAART, there is a higher frequency of HIV DNA in activated as compared to resting CD4+ T cells, which is not readily explained
by activation of infected cells
During HAART, a low CD4 predicts a higher frequency of infected cells and a shift in reservoir toward transitional and effector cells;
this effect that may be due to IL-7 mediated T cell proliferation
Chomont et al, Nature Medicine, 2010
How HIV persists during antiviral therapy?
Viral replication
T cell survival
Proliferation
Nicholas Chomont, 2010
Inflammation may drive HIV persistence through several non mutually exclusive mechanismsseveral non-mutually exclusive mechanisms
Microbial
PD1/PD1L
Microbial translocation, ↑ co-pathogens (CMV), thymic ( ), y
dysfunction, loss of regulatory cells
Homeostatis
HIV replication
Impact of persistent immunodeficiency (as y (defined by peripheral CD4+ T cell count) onCD4+ T cell count) on
HIV persistence
Biology associated with low CD4+ T cells on early HAART (most of whom will eventually reconstitute an effective
Slide #25
1500
( yimmune system) is likely different from will likely prove to be
different than 1500
ount
1000
cell
co
500
D4+
T
0 1 2 3 4 5 6 7 8 9 10 110
CD
Year of suppressive HAARTKelley CF, CID ‘09
Among adults with durable viral suppression, a low CD4+ T cell count is associated with significant immunologic
abnormalities, many of which are associated with CAD
P = 0.0001 P < 0.0001P 0.0001
P < 0.0001 P = 0.05
Hatano CROI 2011
Greater lymphoid aggregate fibrosis maybe primary irrreversible mechanism accounting for persistent
immune dysfunction during HAART
Hunt and Shacker CROI 2011
Plasma RNA Levels May Be Higher in C G
1000
Low CD4 Group
750
RN
AL)
p = 0.09
500
a H
IV R
pies
/mL
250
Plas
m(c
op
Low CD4 High CD40
g
*Excludes 2 outliers3.39 copies/mL vs. 0 copies/mL
Proviral DNA Levels May Be Higher in C G ( C )
25000
Low CD4 Group (per mil CD4)
20000
5000
A D4) p = 0.12
10000
15000
iral
DN
As/
mil
C
5000
10000
Prov
(cop
ies
Low CD4 High CD40
574 copies vs. 240 copies
Cell-associated RNA Levels Much Lower in C G ( C )
7500
Low CD4 Group (per mil CD4)
7500
RN
AD
4) p < 0.0001
5000
iate
d R
mil
CD
2500
asso
ciC
o pe
r
0
Cel
l-a(S
/C
Low CD4 High CD4
0
Therapeutic approachesTherapeutic approaches
Will combination therapy be needed to ti t d th l l t tl i f t d ll ?activate and then clear latently infected cells?
Reversal of host h i ( timechanisms (anti-
PD1, chemokine antagonists, anti-
inflammationinflammation, MCSF inhibition)
Will combination therapy be needed to ti t d th l l t tl i f t d ll ?activate and then clear latently infected cells?
Reversal of host h i ( timechanisms (anti-
PD1, chemokine antagonists, anti-
inflammationinflammation, MCSF inhibition)
↑ DNA transcription via chromatin modification(HDACi, HMTi, NF-kB
activators)
Will combination therapy be needed to ti t d th l l t tl i f t d ll ?activate and then clear latently infected cells?
Reversal of host h i ( timechanisms (anti-
PD1, chemokine antagonists, anti-
inflammation
Clearance of activated cells(therapeutic
iinflammation, MCSF inhibition)
vaccine, immunotoxin)
↑ DNA transcription via chromatin modification(HDACi, HMTi, NF-kB
activators)
Therapuetic Options: HIV replication/persistencep p
• HAART intensification• Reversal of latency
– HDAC inhibitors– Prostratin– Interleukin-7, interleukin-15– Immunomodulatory (anti-PD-1 antibodies)– MCSF inhibitors
• Anti-inflammatory drugs• Stem cell therapy (CCR5 zinc finger, siRNA)Stem cell therapy (CCR5 zinc finger, siRNA)
Therapeutic Options: Inflammation (HIV)• Chemokine receptor inhibitors
– Maraviroc, TB-652• Anti-infective therapy
– HCV, CMV• Microbial translocation
– Sevelamer, colostrum, rifaximin– KGF, glucagon agonists (gut epithelium)
• Enhance T cell renewal – Growth hormone– IL-2, IL-7,– Stem cell transplant
Therapeutic Options: InflammationAnti inflammatory drugs• Anti-inflammatory drugs– Prednisone, hydroxyurea, cyclosporin, mycophenolic acid– Chloroquine hydroxychloroquineChloroquine, hydroxychloroquine– Minocycline– NSAIDs (COX-2 inhibitors), aspirin( ) p– Statins– Methotrexate (low-dose; CIRT) – Talidomide, lenalidomide, pentoxyfylin (weak TNFα
inhibitors)ACE inhibitors angiotensin receptor II antagonists– ACE inhibitors, angiotensin receptor II antagonists (mediated via reduced aldosterone)
• Biologics g– TNF inibitors, IL-6 inhibitors, anti-CD20 ab, abatacept
(CTLA4Ig), IL-1 receptor inhibitor
Therapeutic Options: Fibrosis
• Perfenidone• Lupron• Lupron • Renin-angiotensin-aldosterone blockers
ACE inhibitors angiotensin receptor– ACE inhibitors, angiotensin receptor blockers
• Angiotensin receptor blockers• Angiotensin receptor blockers • Anti-TGFβ antibody
Res eratrol• Resveratrol• Connective tissue growth factor (CTGF)
antibodiesantibodies
In the absence of ongoing viral replication, strong HIV specific T cell responses in the gut mucosa areHIV specific T cell responses in the gut mucosa are
associated with lower levels of viral persistence
1.0L2+
) 6L2+
)
CD4CD8
0.5
cific
IFN
g+ I
cells
(GA
LT
3
4
5
cific
IFN
g+ I
cells
(GA
LT
0.0
% G
ag-s
pec
CD
8+ T
0
1
2
% G
ag-s
pec
CD
4+ T
0 1 2
log10 Proviral DNA(per mil PBMC)
rho = - 0 56 p = 0 01
0 1 2log10 Proviral DNA
(per mil PBMC)
rho = - 0 37 p = 0 12rho = - 0.56, p = 0.01 rho = - 0.37, p = 0.12
Hatano et al.; JID 11
Can HIV-associated Can HIV-associated inflammation can not
yet be treated, can it be inflammation can not
yet be treated, can it be yprevented?
yprevented?
CD8+ T cell activation after long-term HAART is lower but not normal in those who startedlower but not normal in those who started
therapy during recent infection than those who started during late infection
090
100
) p=0.024
5060
7080
+/H
LA-D
R+
p=0.039
p=0.0009
2030
40
% (C
D38
+0
10
excludes outside values
Acute HIV
NoART
EarlyART
LaterART
HIVNeg.
Jain et al, CROI 11
g
(at maximum time observed)
Cell-associated DNA and RNA also lower after l t HAART th t ti llong-term HAART among those starting early
versus late
On-ART Proviral DNA Levels
4
On-ART Cell-assoc. RNA Levels
30
(PV-
DN
A)
23
020
RN
A (S
/Co)
Log(
01
excludes outside values
1Y M 1Y M0
10
CA
-Rexcludes outside values
1Y M 1Y M1Y ART
Max ART
Early ART Start
Later ART Start
1Y ART
Max ART
1Y ART
Max ART
Early ART Start
Later ART Start
1Y ART
Max ART
Jain et al. (CROI 2011)
Conclusions• Although there is no consistent association
between plasma HIV RNA levels and any h t thhost-response or therapy-response (intensification) in blood, there emerging data suggesting associations in GALTdata suggesting associations in GALT
• Data collectively support possible role of residual viral replication in tissues as causeresidual viral replication in tissues as cause of inflammation and a barrier to eradication
• Despite a growing consensus that this• Despite a growing consensus that this question has been resolved, t here remains several critical unanswered questions q
Conclusions• Multiple mechanisms might account for how an
inflammatory environment—which likely persists in all individuals—might contribute to persistenceall individuals might contribute to persistence• Increased target susceptibility• Increased homeostatic expansionIncreased homeostatic expansion• Upregulation of negative activator of T cell
activation (e.g., PD-1, CTLA-4)• Reduced clearance of virus by host mechanisms
• Immune-based therapeutics that address these host responses may have benefits on inflammation-associated disease and size of the latent reservoirC ti t t i d t b i di id li d• Curative strategies may need to be individualized based on CD4+ T cell count and other measures
AcknowledgementsElsewhereSCOPE Cohort / UCSF NIAID RO1 ElsewhereNetanya SanderDanny DouekMichael Lederman
SCOPE Cohort / UCSFJeff Martin David NaegerRebecca Hoh
AI087145, K24AI069994,
CNICS (5R24AI067039)Michael Lederman
Alan LandayRussell TracyApril Ferre
Rebecca HohRick HechtVivek JainHarry Lampiris
(5R24AI067039), CLIC
pBarbara ShacklettTim ShackerLarry Corey
y pAmanda SchnellSteven YuklJoe Wong
Robert KaplanNiicolas ChomontRafick Sekaly
Tzong-Hae LeeMichael BuschElizabeth SinclairLorrie EplingLorrie EplingMike McCune