immune-based interventions for hiv infection and aids
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/1.jpg)
Immune-Based Interventions for HIV Infection and AIDS
Alan Landay, PhDProfessor and Chairman
Department of Immunology/MicrobiologyRush University Medical Center
Chicago, Illinois
![Page 2: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/2.jpg)
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
![Page 3: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/3.jpg)
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
![Page 4: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/4.jpg)
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
![Page 5: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/5.jpg)
Therapies for Restoring Immunodeficiency
• CytokinesIL2, IL7, IL12, GM-CSF
• Therapeutic Vaccines
![Page 6: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/6.jpg)
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
![Page 7: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/7.jpg)
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)
![Page 8: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/8.jpg)
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
![Page 9: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/9.jpg)
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
![Page 10: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/10.jpg)
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
![Page 11: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/11.jpg)
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)
![Page 12: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/12.jpg)
Immune Activation Inflammation
![Page 13: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/13.jpg)
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?
![Page 14: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/14.jpg)
blood 8 JANUARY 2009 I VOLUME 113, NUMBER 2:269
TLR-mediated immune activation in HIV
![Page 15: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/15.jpg)
Good IFN- a turns bad
![Page 16: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/16.jpg)
0500
100015002000250030003500
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
![Page 17: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/17.jpg)
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
D38
+HLA
DR
+ of
CD
8 Tc
ells
p=0.0197 p=0.0176
0
100
200
300
400
500
600
700
CD
38 M
FI C
D8
Tcel
ls
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
![Page 18: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/18.jpg)
SMART: Inflammatory Markers Strongly Associated With Mortality and CVD Events
BiomarkerAll-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 0.56Kuller LH, et al. PLoS Med. 2008 ;5: e203. doi:10.1371/journal.pmed.0050203.
![Page 19: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/19.jpg)
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
![Page 20: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/20.jpg)
Approaches to BlockActivation/inflammation & Microbial Translocation
Chloroquine : Activation inhibitorStatins/anti-IL-6: Inflammation inhibitorsRifaxamin/Sevalamer: MT inhibitors
![Page 21: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/21.jpg)
Immune-activationCD4 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
![Page 22: Immune-Based Interventions for HIV Infection and AIDS](https://reader036.vdocument.in/reader036/viewer/2022062310/56816666550346895dd9fa11/html5/thumbnails/22.jpg)
RushSeema DesaiJeff Martinson
NIAIDIrini SeretiLarry Fox
Netanya Sandler
CaseMichael Lederman