Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division.
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Interventions to Reduce Inflammation
and Immune Activationin Treated HIV Infection
Peter W. Hunt, MD
Assistant Professor of Medicine
UCSF HIV/AIDS Division
Treating Immune Activation in HIV• What have we learned from recent
unsuccessful attempts?
• Mechanistic pathways of HIV pathogenesis inform therapeutic interventions.
• Highlight ongoing and recently reported studies of novel interventions.
– Importance of studying ART-suppressed patients
• A way forward
IL-2 Increases CD4 Counts in Treated Patients
Abrams et al, NEJM, 2009
IL-2 also decreases HLA-DR and CD38 expression(Kovacs, NEJM, 1995)
Why Didn’t IL-2 Work?
IL-2
Preferential Expansion
of Tregs
Suppression of Healthy T Cell
Responses
Increased CD4 Count Good for
Health
Bad for Health
Maraviroc Intensification Increases CD8 Activation Compared to Placebo
Hunt, CROI, 2011, Abstract 153LB
>2-fold Increase in Plasma CCR5 Ligand Levels During Maraviroc Intensification
• Due to prevention of ligand-receptor complex internalization by CCR5+ cells (Lin/Corbeau, AIDS, 2007; Nakata, Antiviral Threrapy, 2010)
• RANTES/MIP-1a may activate monocytes/macrophages and neutrophils via CCR1
What Have We Learned?
• Immune system is complicated!
– Multiple parallel and competing pathways, feedback loops
• Primary effects assessed in vitro may fail to capture important competing secondary effects in vivo
• Need for carefully designed placebo-controlled trials, follow up studies to elucidate these mechanisms
• May need to improve more than surrogate inflammatory markers to advance to clinical endpoint trials (i.e., FMD, BMD, etc).
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Anti-LPS antibodies have no effect on CD4 recovery: CORAL
HIV+On cART
CD4<350 cells/ul∆CD4<50 past 12 months
Raltegravir HIBC+
placebo HIBC+
Raltegravir placebo+
placebo placebo+
HIBC= hyperimmune bovine colostrumEnriched in anti-LPS antibodies
n=18
n=18
n=18
n=18RESULTSNo effect on CD4 recoveryNo effect on LPS, sCD14, T cell activation
Bykawaga et al, J Infect Dis 2011 (in press) Slide courtesy of Sharon Lewin
Microbial Translocation:Cause or Consequence of Immune Activation
in Treated HIV Infection?
• Observational studies linking MT to immune activation cannot prove causality– Causality can only be formally addressed in clinical trials
• DC/Macrophage activation can cause IDO induction, ↓Th17, and microbial translocation
• Ongoing/Planned studies assessing blocking microbial translocation directly– Rifaximin (ACTG)
– Sevalamer (ACTG)
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Chloroquine Might Reduce CD8 Activationin Untreated HIV+ Patients
Chloroquine Placebo
Murray, JV, 2010
• No apparent effect on plasma HIV RNA Levels (though some missing data)• Possible early decrease in plasma LPS• Probable mechanism: TLR inhibition (3,4,7,8,9)
Hydroxychloroquine Did Not Reduce CD8 Activation in Untreated HIV+ Patients
%CD38+HLA-DR+ CD8s
Paton, IAS 2011, MOPE269
Why did viral load increase with HCQ?
And why didn’t CD8 activation increase with the increase in VL?
Viral Load
-.1
0
.1
.2
.3
.4
Me
an
(p
oin
twis
e 9
5%
CI)
0 12 24 36 48Weeks from randomisation
HCQ Placebo
Change in lrna from randomisation: by Arm
Pla
sma
HIV
RN
A L
evel
(lo
g10
co
pie
s/m
l)
-10
-5
0
5
Me
an (
poi
ntw
ise
95%
CI)
0 12 24 36 48Weeks from randomisation
HCQ Placebo
Change in cd8cd38DR_p from randomisation: by Arm
Impact of Innate Immune ResponseUntreated HIV Disease
The Bad:
Immune Activation ↑
The Good:
HIV replication ↓
Direct Antiviral Effects
Adjuvant to HIV-specific T cells
IL-6, TNFα↑
TF expression, D-dimer ↑
T cell turnover/exhaustion ↑
LN fibrosis ↑
Immune Activation ↓
Impact of Innate Immune ResponseDuring ART-mediated VL Suppression
The Good: None
VL already suppressed by
drugs
Antiviral Effects Irrelevant
The Bad
Immune Activation ↑
IL-6, TNFα↑
TF expression, D-dimer ↑
T cell turnover/exhaustion
LN fibrosis
HCQ Decreases Immune Activation in ART-suppressed Immunologic Non-responders
%CD38+ Memory CD8s
Piconi, Blood, 2011
%CD69+ CD14+ Monocytes
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation
in HIV+ Patients with CD4<350 despite ART
-4.4%
HIV-Median
Hunt et al, JID, 2011
• Cytopenias may limit long-term usefulness.
• Need new, safer CMV agents!
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyBacterial
TranslocationViral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
Atorvostatin Decreases T Cell Activation in Untreated HIV Infection
Atorvostatin 80mg
Placebo
Ganesan, J Infect Dis, 2011
• 24 untreated patients, X-over design
• Significant reduction in HLA-DR on CD8s during atorvostatin Tx
• No effect on plasma HIV RNA levels
• Studies ongoing in ART-suppressed patients
COX-2 Inhibition Decreases T Cell Activation in Untreated HIV Infection
• 27 untreated patients, 12 weeks celecoxib vs. placebo.
• Significant reduction in CD38 on CD8s during celecoxib Tx
• No effect on plasma HIV RNA levels
• CAD toxicity a potential problem with celecoxib
• ASA? Mesalamine?
CD
38
Mo
lec
ule
s/c
ell
Pettersen, JV, 2011
CelecoxibPlacebo
Other Strategies to block Monocyte/Macrophage Activation?
• Combined CCR5/CCR2 blockade?– CCR5 inhibition increased immune activation, likely
indirectly through MØ activation
– CCR2 (MCP-1 receptor) blockade might overcome this effect?
• IDO inhibitors?– Prevent proliferative defects and allow for restoration
of Th17 cells
– Might interrupt vicious circle of microbial translocation and innate immune activation
Immunosuppressive Therapies
Suppression of Healthy Immune Reponses
DecreasedImmune Activation
The Good The Bad
TNFα inhibitors IL-6 inhibitors
CTLA-4 analogs IL-23/IL-12 inhibitors
Steroids Cyclosporine
Methotrexate
A Way Forward…• Target proximal causes of monocyte activation
• Small pilot trials to establish proof of principal– “Immunologic Non-Responders” have higher immune
activation and are at highest risk for disease
– Studying treated patients allows cleaner biologic inferences
– Need to thoroughly evaluate mechanistic pathways in vivo
• Advance promising agents to mid-range trials with surrogate markers of end-organ disease– Liver, renal, bone (BMD), cardiovascular (FMD)
• Advance promising/safe/scalable interventions to clinical endpoint trials
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