Role of Adaptive vs. Innate Immune Activation innon-AIDS Morbidity

Peter W. Hunt, MDAssociate Professor of Medicine

UCSF HIV/AIDS Division

A shift in focus…

• T cell activation as a target for interventions in the pre-ART era

• Monocyte activation and inflammation a target during treated HIV disease

• Why this shift is occurring– Important caveats

• Implications for future clinical trials

Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency

MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon

Dec 10, 1981

T10=CD38

Leu3=CD4

CD8+ T cell activation predicts survival better than VL

in patients with AIDS (CD4<200)

Janice Giorgi

Giorgi, JID, 1999 (see also: Giorgi, JAIDS, 2002)

Survival

P=0.02

Survival

P=0.001

T Cell Activation Declines with ART

Hunt et al, JID, 2003; PLoS One, 2011

But Remains Abnormally High During ART-mediated Viral Suppresion

Hunt et al, JID, 2003; PLoS One, 2011

Is T cell activation a cause of disease in treated HIV infection or

simply a marker for some other process?

Important for identifying targets for novel interventions

Low CD4 Count during ART Predicts non-AIDS Death

Young et al for COHERE cohort, PLoS Med, 2012 (see also Baker, AIDS, 2008)

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)

However, IL-2 Had No Effect on AIDS/Death

Abrams et al, NEJM, 2009

P=0.47

P=0.55

CD4 count (and CD38 / DR expression) is not 100% specific for the pathophysiologic pathway mediating disease.

Why didn’t IL-2 work?

• May have expanded the wrong type of CD4+ T cells (regulatory cells).– Impaired functional immune responses?

• Could CD4+ T cell count just be a marker for some other immunologic process?

What Specific Immunologic Pathways are Driving Disease during ART?

Non-AIDSMorbidity /Mortality

Innate Immune Activation(MØ/DC)

CD4Lymphopenia

Inflammation

T and B CellActivation/

Dysfunction

?

?

?

Coagulation ?

What Specific Immunologic Pathways are Driving Disease during ART?

Non-AIDSMorbidity /Mortality

Innate Immune Activation(MØ/DC)

CD4Lymphopenia

Inflammation

T and B CellActivation/

Dysfunction

?

?

?

Coagulation ?

X

Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)

High T Cell Activation Associated with Blunted CD4 Recovery during ART

Lederman et al., JID, 2011

Inflammation and Innate Immune Activation are Increased in Patients with

Poor CD4+ T cell Recovery on ARTIL-6 sCD14

CD4<350 CD4>500 HIV- CD4<350 CD4>500 HIV-

How do we get a better sense of the specific immunlogic

pathways driving disease?

Eden et al., JID , 2007 (see also: Burdo, AIDS, 2013; Lyons, JAIDS, 2011; Letendre, CROI 2012, Abstract #82)

Abnormal CSF Neopterin Levels Persist Despite 4 Years of VL Suppression

60% Abnormal

Sinclair, JAIDS, 2008

CD8+ T Cell Activation is Not Persistently Elevated in CSF During Suppressive ART

T cell activation in the CNS is unlikely to explain persistent neurocognitive dysfunction in ART-suppressed individuals

Baker, CROI 2013, Abstract #66LB

Monocyte Activation Predicts Coronary Artery Calcium Progression: SUN Study

T cell Activation

Not Predictive

Do these markers predict clinical events?

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 3.1 0.02 1.6 0.20

IL-6 12.4 <0.0001 2.8 0.003

Amyloid A 3.1 0.05 1.6 0.12

Amyloid P 1.1 0.78 2.8 0.002

D-dimer 41.2 <0.0001 2.0 0.06

F1.2 1.3 0.64 0.8 0.56

Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009Even after adjusting for CD4 count!

Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)

Innate Immune Activation Predicts Mortality More Strongly than T Cell Activation: SOCA

Gut Epithelial Barrier Dysfunction

Inflammation / Coagulation

Matched for age, gender, duration VL suppression, CMV retinitis, nadir CD4

IDO-1 Induction

Monocyte Activation

Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)

Innate Markers Predict Mortality Independent of Nadir AND Current CD4 count

Gut Epithelial Barrier Dysfunction

Inflammation / Coagulation

Also adjusted

for currentCD4

count

IDO-1 Induction

Monocyte Activation

Current CD4 count no longer predictive of mortality after

adjusting for innate markers

Why does T cell “senescence” not predict mortality in HIV

infection?

Antigen

CD57+,↓Telomere

Length

A: Normal CD8+ T Cell Proliferation & Maturation

Central Memory Transitional TEMRAEffector Memory

CD28- Memory CD8+ CellsCD28+CD27+CCR7+RA- CD27+CCR7-RA- CD27-CCR7-RA- CD27-CCR7-RA+

CD57-,↑Telomere

Length

Antigen

Inflammatory Cytokines

B: Maturational/Proliferative Defect in HIV

IDO-1,PD-1+ Monocytes

Central Memory Transitional TEMRAEffector Memory

CD28- Memory CD8+ CellsCD28+CD27+CCR7+RA- CD27+CCR7-RA- CD27-CCR7-RA- CD27-CCR7-RA+

Lee, CROI 2013, #294

Antigen

CD57+,↓Telomere

Length

A: Normal CD8+ T Cell Proliferation & Maturation

Central Memory Transitional TEMRAEffector Memory

CD28- Memory CD8+ CellsCD28+CD27+CCR7+RA- CD27+CCR7-RA- CD27-CCR7-RA- CD27-CCR7-RA+

CD57-,↑Telomere

Length

Antigen

Inflammatory Cytokines

B: Maturational/Proliferative Defect in HIV

IDO-1,PD-1+ Monocytes

Central Memory Transitional TEMRAEffector Memory

CD28- Memory CD8+ CellsCD28+CD27+CCR7+RA- CD27+CCR7-RA- CD27-CCR7-RA- CD27-CCR7-RA+

Lee, CROI 2013, #294

HIV Disease Drives Expansion of CD28- CD8+ T Cells . . .

All CMV+ Lee, CROI 2013, #309

P=0.0002P=0.10

But CD57 is inappropriately low onCD28- CD8+ T Cells in HIV infection

All CMV+ Lee, CROI 2013, #309

P<0.0001P=0.0003

Low (Not High) CD57 on CD28- CD8+ T Cells Predicts Mortality in Treated HIV

*Subjects matched on age, gender, duration of viral suppression, presence of CMV retinitis, and nadir CD4+ cell count Lee, CROI 2013, #309

Higher Monocyte Activation Associated with the Low CD57 CD8+ T cell Defect

Lee, CROI 2013, #309

Monocyte activation may cause T cell proliferative defects in HIV by:

• PD1-driven IL-10 release (Said, Nat Med, 2010)

• IDO-1 induction (Boasso, Blood, 2007)

What Specific Immunologic Pathways are Driving Disease during ART?

Non-AIDSMorbidity /Mortality

Innate Immune Activation(MØ/DC)

CD4Lymphopenia

Inflammation

T and B CellActivation/

Dysfunction

?

?

Coagulation

Caveats…

T / B Cell Activation Predicts NHL (MACS)

Breen, Cancer Epi Bio, 2011

Adjusted for age, duration HIV infection, and CD4 count

T Cell Activation may be an important contributor to HIV reservoir size…

Hatano, JID, 2013

Implications for Clinical Trials

CD8 Activation is a Reproducible and Responsive Marker

Hunt, Blood, 2013

Placebo Arm

Std Devof ∆ Wk 0-24:

0.13 log10%

~35% relative

change

Lots of Within-subject Variability in IL-6

Std Devof ∆ Wk 0-24:

0.38 log10pg/ml

~2.4-fold relative change

Hunt, Blood, 2013

sCD14 is much better, comparable variability to T cell activation

Std Devof ∆ Wk 0-24:

0.11 log10ug/ml

~29%relative change

Hunt, Blood, 2013

• Several immunologic defects predict disease in treated HIV infection:– Innate immune activation and inflammation– CD4 lymphopenia– T cell / B bell activation and dysfunction

• Innate immune activation and inflammation independently predict disease, less consistent for other markers.

• Interventions designed to decrease activation of myeloid lineage cells may hold promise.– Statins, ASA?– Microbial Translocation interventions– Treating co-infections?

Summary

AcknowledgementsNIAIDJason BrenchleyDanny DouekIrini Sereti

Core Immunology Lab/DEMElizabeth SinclairLorrie EplingMike McCune

SOCACurtis MeinertMark Van Natta

ACTGHeather Ribaudo

SCOPE/OPTIONS/UCSFSulggi LeeSteve DeeksJeff Martin Hiroyu HatanoVivek JainRebecca HohRick Hecht

CWRUWei JiangMichael LedermanNick FunderburgBrian Claggett

U MinnesotaJason Baker

R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA