immune-based interventions for hiv infection and aids alan landay, phd professor and chairman...
TRANSCRIPT
Immune-Based Interventions for HIV Infection and AIDS
Alan Landay, PhDProfessor and Chairman
Department of Immunology/MicrobiologyRush University Medical Center
Chicago, Illinois
Immune Based Therapy1981-2011
Early years (1985-1995) mono and dual lead to suboptimal immune restorationHAART (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
HIV Replication in CD4 cells
Immunodeficiency OI/AIDS
Immune Activation Inflammation
HAART
Restore CD4TCell Number & function
ReduceCD4 & CD8 T Cell activationNot normalized
CVD Bone Renal Neurocog & Cancers
IL2 Phase III StudiesSILCAAT(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=8P = 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 VaccinesWhere 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
interruptionWhere 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)
What’s Driving Immune Activation During Treated HIV Infection?
• Low-level HIV replication or release?• HIV Driven Interferon Alpha Production?• Microbial Translocation?• Co-Infections (CMV or HCV)?• Homeostatic Proliferation?
0
500
1000
1500
2000
2500
3000
3500
Media CpG-B CpG A TLR 7/8 HIV-Ada HIV-MN
No Chloroquine
100 µM Chloroquine
IFN
-a p
g/m
lChloroquine abrogates IFN-a production in vitro
Martinson J et al Antimicrob Agent Chemother 2010, 54(2):871–881
Chloroquine downmodulates both % and per cell expression of activation markers CD38 +HLADR+ cells in CD8+ T cells
Media AT2-Ada AT2-MN MV-R5 MV-X40.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
%C
D3
8+
HL
A D
R+
of
CD
8 T
ce
lls
p=0.0197 p=0.0176
0
100
200
300
400
500
600
700
CD
38
MF
I C
D8
Tc
ell
s
p=0.0020 p=0.0051
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- HIV+
Loss of CD4+ T cells
Enterocyte apoptosis
Loss of tight junctions
Microbial translocation
Brenchley & Douek, Mucosal Immunol, 2008
Gut lumen
LipopolysaccharideIntestinal fatty acidbinding protein (I-FABP)
Gut parenchyma
Approaches to BlockActivation/inflammation & Microbial Translocation
Chloroquine : Activation inhibitorStatins/anti-IL-6: Inflammation inhibitorsRifaxamin/Sevalamer: MT inhibitors
Immune-activation
CD4 Responders
CD4 Non-Responders
Viral LoadRel
ativ
e v
alue
s
Diagnosis Time on HAART in years
Chloroquine/Rifaxamin/Sevalamer?Statin + HAARTIL-7+HAART
Therapeutic vaccine (?)
Hope for the future: Targeting Immune-deficiency Immune-restoration & Immune-activation
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