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Role of Adaptive vs. Innate
Immune Activation in
non-AIDS Morbidity
Peter W. Hunt, MD
Associate 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
Dec 10, 1981
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
Leu3=CD4
T10=CD38
CD8+ T cell activation predicts
survival better than VL
in patients with AIDS (CD4<200)
P=0.001
Janice Giorgi
P=0.02
Survival
Survival
Giorgi, JID, 1999 (see also: Giorgi, JAIDS, 2002)
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
IL-2 also decreases HLA-DR
and CD38 expression
(Kovacs, NEJM, 1995)
Abrams et al, NEJM, 2009
However, IL-2 Had No Effect on
AIDS/Death
P=0.47
CD4 count (and CD38 / DR
expression) is not 100%
specific for the
pathophysiologic pathway
mediating disease.
P=0.55
Abrams et al, NEJM, 2009
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?
CD4
Lymphopenia
Innate Immune
Activation
(MØ/DC)
?
Inflammation
?
Coagulation
?
T and B Cell
Activation/
Dysfunction
?
Non-AIDS
Morbidity /
Mortality
What Specific Immunologic Pathways
are Driving Disease during ART?
CD4
Lymphopenia
Innate Immune
Activation
(MØ/DC)
?
Inflammation
?
Coagulation
?
T and B Cell
Activation/
Dysfunction
?
Non-AIDS
Morbidity /
Mortality
High T Cell Activation Associated with
Blunted CD4 Recovery during ART
Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)
Inflammation and Innate Immune
Activation are Increased in Patients with
Poor CD4+ T cell Recovery on ART
IL-6
CD4<350
CD4>500
sCD14
HIV-
CD4<350
CD4>500
HIV-
Lederman et al., JID, 2011
How do we get a better sense of
the specific immunlogic
pathways driving disease?
Abnormal CSF Neopterin Levels Persist
Despite 4 Years of VL Suppression
60%
Abnormal
Eden et al., JID , 2007 (see also: Burdo, AIDS, 2013; Lyons, JAIDS, 2011; Letendre, CROI 2012, Abstract #82)
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
Sinclair, JAIDS, 2008
Monocyte Activation Predicts Coronary
Artery Calcium Progression: SUN Study
T cell
Activation
Not Predictive
Baker, CROI 2013, Abstract #66LB
Do these markers predict
clinical events?
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
3.1
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
Even after adjusting for CD4 count!
Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009
Innate Immune Activation Predicts Mortality
More Strongly than T Cell Activation: SOCA
Gut Epithelial
Barrier Dysfunction
IDO-1 Induction
Monocyte Activation
Inflammation /
Coagulation
Matched for age, gender,
duration VL suppression,
CMV retinitis, nadir CD4
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
IDO-1 Induction
Monocyte Activation
Inflammation /
Coagulation
Current CD4 count no longer
predictive of mortality after
adjusting for innate markers
Also
adjusted
for current
CD4
count
Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)
Why does T cell “senescence”
not predict mortality in HIV
infection?
A: Normal CD8+ T Cell Proliferation & Maturation
CD57-,
CD57+,
↑Telomere
↓Telomere
Length
Length
Antigen
B:
CD28- Memory CD8+ Cells
CD28+CD27+
Maturational/Proliferative
Defect in
HIV
CD27-CCR7-RACD27+CCR7-RACD27-CCR7-RA+
CCR7+RACentral Memory
Transitional
Effector Memory
TEMRA
Inflammatory
Cytokines
Antigen
IDO-1,
PD-1+ Monocytes
CD28+CD27+
CCR7+RACentral Memory
CD28- Memory CD8+ Cells
CD27+CCR7-RATransitional
CD27-CCR7-RAEffector Memory
CD27-CCR7-RA+
TEMRA
Lee, CROI 2013, #294
A: Normal CD8+ T Cell Proliferation & Maturation
CD57-,
CD57+,
↑Telomere
↓Telomere
Length
Length
Antigen
B:
CD28- Memory CD8+ Cells
CD28+CD27+
Maturational/Proliferative
Defect in
HIV
CD27-CCR7-RACD27+CCR7-RACD27-CCR7-RA+
CCR7+RACentral Memory
Transitional
Effector Memory
TEMRA
Inflammatory
Cytokines
Antigen
IDO-1,
PD-1+ Monocytes
CD28+CD27+
CCR7+RACentral Memory
CD28- Memory CD8+ Cells
CD27+CCR7-RATransitional
CD27-CCR7-RAEffector Memory
CD27-CCR7-RA+
TEMRA
Lee, CROI 2013, #294
HIV Disease Drives Expansion
of CD28- CD8+ T Cells . . .
% CD28of CD8+ T Cells
% CD28of CD8+ T cells
100
P=0.0002
P=0.10
80
60
40
20
0
HIV-
All CMV+
HIV+
ART+
VL<75
HIV+
ARTVL>10K
Lee, CROI 2013, #309
But CD57 is inappropriately low on
CD28- CD8+ T Cells in HIV infection
% CD57+
of CD28-CD8+ T Cells
% CD28of CD8+ T Cells
% CD57+
of CD28-CD8+ T cells
% CD28of CD8+ T cells
100
80
60
40
20
0
HIV-
All CMV+
HIV+
ART+
VL<75
HIV+
ARTVL>10K
P<0.0001
P=0.0003
100
80
60
40
20
0
HIV-
HIV+
ART+
VL<75
HIV+
ARTVL>10K
Lee, CROI 2013, #309
Low (Not High) CD57 on CD28- CD8+ T
Cells Predicts Mortality in Treated HIV
%CD57+ on
CD28-CD8+ T Cells
4th Quartile
3rd Quartile
1.0
1.14
4.41
2nd Quartile
4.97
1st Quartile
0.1
1
10
100
Odds of Mortality
(compared to 4th Quartile)
*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
% CD57+
of CD28- CD8+ T Cell
SOCA
100
Spearman's rho: -0.24, P=0.002
80
60
Monocyte activation may
cause T cell proliferative
defects in HIV by:
• PD1-driven IL-10 release
40
(Said, Nat Med, 2010)
• IDO-1 induction
20
(Boasso, Blood, 2007)
0
900
1900
2900
3900
4900
sCD14 Level (ug/ml)
Lee, CROI 2013, #309
What Specific Immunologic Pathways
are Driving Disease during ART?
CD4
Lymphopenia
Innate Immune
Activation
(MØ/DC)
?
Inflammation
Non-AIDS
Morbidity /
Mortality
Coagulation
T and B Cell
Activation/
Dysfunction
?
Caveats…
T / B Cell Activation Predicts NHL (MACS)
Adjusted for age, duration HIV
infection, and CD4 count
Breen, Cancer Epi Bio, 2011
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
Placebo Arm
Std Dev
of ∆ Wk 0-24:
0.13 log10%
~35%
relative
change
Hunt, Blood, 2013
Lots of Within-subject Variability in IL-6
Std Dev
of ∆ 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 Dev
of ∆ Wk 0-24:
0.11
log10ug/ml
~29%
relative
change
Hunt, Blood, 2013
Summary
• 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?
Acknowledgements
SCOPE/OPTIONS/UCSF
Sulggi Lee
Steve Deeks
Jeff Martin
Hiroyu Hatano
Vivek Jain
Rebecca Hoh
Rick Hecht
CWRU
Wei Jiang
Michael Lederman
Nick Funderburg
Brian Claggett
U Minnesota
Jason Baker
NIAID
Jason Brenchley
Danny Douek
Irini Sereti
Core Immunology Lab/DEM
Elizabeth Sinclair
Lorrie Epling
Mike McCune
SOCA
Curtis Meinert
Mark Van Natta
ACTG
Heather Ribaudo
R56AI100765, 1R21AI087035,
1R21AI07877, DDCF CSDA