Immune-Based Interventions for HIV Infection and AIDS Alan Landay, PhD Professor and Chairman Department of Immunology/Microbiology Rush University Medical.

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

Therapies for Restoring Immunodeficiency

• CytokinesIL2, IL7, IL12, GM-CSF

• Therapeutic Vaccines

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)

Immune Activation Inflammation

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?

blood 8 JANUARY 2009 I VOLUME 113, NUMBER 2:269

TLR-mediated immune activation in HIV

Good IFN- a turns bad

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

RushSeema DesaiJeff Martinson

NIAIDIrini SeretiLarry Fox

Netanya Sandler

CaseMichael Lederman