Role of Adaptive vs. Innate Immune Activation in non-AIDS Morbidity Peter W. Hunt, MD Associate Professor of Medicine UCSF HIV/AIDS Division
Feb 24, 2016
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