Transcript Document

Immune-Based Interventions for
HIV Infection and AIDS
Alan Landay, PhD
Professor and Chairman
Department of Immunology/Microbiology
Rush University Medical Center
Chicago, Illinois
Immune Based Therapy
1981-2011
Early years (1985-1995) mono and dual lead to suboptimal immune
restoration
HAART (1995) reduced morbidity and mortality with sustained viral
suppression and CD4 T cell increase and evidence of functional immune
reconstitution
 Post HAART (2000) cytokines and therapeutic vaccines were proposed to
restore immunity
The SMART Study (2006) demonstrated the importance of immune
activation/inflammation to non HIV co-morbidities and a focus on therapeutic
agents to block inflammatory pathways
Impact of HAART on Immune System
• Restoration of CD4 T cell number and function based on nadir CD4
count however 5-30% of subjects did not demonstrate increase in
CD4 T cell numbers
• Reduction of CD8 T cell activation but level isn't normalized
despite viral control
• Some improvement in APC function but not full reconstitution to
level of HIV negative control
Need for strategies that target immune deficiency
and immune activation
HIV The Immune System and HAART
Immunodeficiency
OI/AIDS
HIV
Replication in
CD4 cells
Restore CD4T
Cell Number
& function
HAART
Immune Activation
Inflammation
Reduce
CD4 & CD8 T
Cell activation
Not normalized
CVD Bone Renal Neurocog & Cancers
Therapies for Restoring
Immunodeficiency
• Cytokines
IL2, IL7, IL12, GM-CSF
• Therapeutic Vaccines
IL2 Phase III Studies
SILCAAT(CD4 50-300 cells/µl) and ESPRIT(CD4 >300 cells/µl)
Median CD4+ Cell Counts during the Study Period, according to
Study and Treatment Group
N Engl J Med 2009;361:1548-59
However
• No clinical Benefit of IL2 on OI or Death
• More Grade 4 Events in ESPRIT (many
thrombotic)
• CD4 T cells that increased were T regulatory
cells(CD25+FOXP3+) that may have
contributed to clinical progression (Levy et al
PNAS 2010)
• IL2 increases inflammatory markers(hsCRP
and D Dimer) that impact non infectious
complications(Porter et al AIDS 2009)
Immune deficiency: Is IL 7 an
answer???
Good toxicity profile and active at low
doses
Expansion of both naïve and central
memory CD4 and CD8 T cells and not T-regs
Minimal T cell activation during cycle
Changes in CD4 and CD8 T cells
* Wilcoxon test
P =0.006, CYT107 10µg/kg, n=7
P=0.004, CYT107 20 µg/kg, n=8
P = 0.008 CYT107 30 µg/Kg, n=6
Placebo, n=6
CYT107 treatment increases T cell number in a dose
dependent manner
Levy Y, ICAAC 2009
Therapeutic Vaccines
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Where we want to go
Need to induce durable T cell response
Need to optimize CD8 T cell response
Need to enhance innate immune response, i.e. DC and NK
Control of HIV replication following therapeutic
interruption
Where are we
No Therapeutic Immunization strategy has produced
robust HIV Control following Analytic Treatment
Interruption
Role of neutralizing antibody not clear
Why Haven’t We Succeded
• Haven't found appropriate immunogen
• Lack of enhancement of APC function
• Induction of regulatory cells(Tregs or MSDC) that
blunt T cell responses
• Persistence of immune dysfunctional molecules on
CD4 and CD8 effectors(PD1 , CTLA-4)
Immune Activation
Inflammation
What’s Driving Immune Activation
During Treated HIV Infection?
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Low-level HIV replication or release?
HIV Driven Interferon Alpha Production?
Microbial Translocation?
Co-Infections (CMV or HCV)?
Homeostatic Proliferation?
TLR-mediated immune activation in HIV
blood 8 JANUARY 2009 I VOLUME 113, NUMBER 2:269
Good IFN- a turns bad
Chloroquine abrogates IFN-a production in vitro
No Chloroquine
100 µM Chloroquine
IFN-a pg/ml
3500
3000
2500
2000
1500
1000
500
0
Media
CpG-B
CpG A
TLR 7/8 HIV-Ada HIV-MN
Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
700
p=0.0197
p=0.0176
CD38 MFI CD8 Tcells
%CD38+HLA DR+ of CD8 Tcells
Chloroquine downmodulates both % and per cell expression
of activation markers CD38 +HLADR+ cells in CD8+ T cells
p=0.0020
p=0.0051
600
500
400
300
200
100
Media
AT2-Ada
AT2-MN
MV-R5
MV-X4
0
Media
AT2-Ada
AT2-MN
MV-R5
MV-X4
No Chloroquine
Chloroquine
Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881
SMART: Inflammatory Markers Strongly
Associated With Mortality and CVD Events
Biomarker
All-Cause Mortality
(N=85)
Fatal or Non-fatal CVD
(N=136)
OR
P-value
OR
P-value
hs-CRP
3.5
0.004
1.6
0.20
IL-6
12.6
<0.0001
2.8
0.003
Amyloid A
2.3
0.08
1.6
0.12
Amyloid P
1.1
0.90
2.8
0.002
D-dimer
13.3
<0.0001
2.0
0.06
F1.2
1.4
0.45
0.8
0.56
Kuller LH, et al. PLoS Med. 2008 ;5: e203. doi:10.1371/journal.pmed.0050203.
HIV Causes Disruption of the Gastrointestinal Tract
HIV-
Loss of tight junctions
HIV+
Gut lumen
Loss of
CD4+ T cells
Gut parenchyma
Enterocyte apoptosis
Intestinal fatty acid
binding protein (I-FABP)
Microbial translocation
Lipopolysaccharide
Brenchley & Douek, Mucosal Immunol, 2008
Approaches to Block
Activation/inflammation & Microbial Translocation
Chloroquine : Activation inhibitor
Statins/anti-IL-6: Inflammation inhibitors
Rifaxamin/Sevalamer: MT inhibitors
Hope for the future: Targeting Immune-deficiency
Immune-restoration & Immune-activation
Chloroquine/Rifaxamin/Sevalamer
?Statin + HAART
Relative values
IL-7+HAART
CD4 Responders
Immune-activation
CD4 Non-Responders
Viral Load
Therapeutic vaccine (?)
Diagnosis
Time on HAART in years
Desai S, adaptation : “Treatment Paradigms in HIV disease”
From Marie-Lise Gougeon Nature Reviews Immunology , 2003; Sereti I Blood 2009, Catalfamo M, JI 2011, Dinoso JB,
PNAS,2009
Rush
Seema Desai
Jeff Martinson
NIAID
Irini Sereti
Larry Fox
Netanya Sandler
Case
Michael Lederman