Immunopathogenesis of AIDS, an
historical perspective:
Or
30 years in 15 minutes
Michael M. Lederman, MD
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
An outbreak of community-acquired Pneumocystis carinii pneumonia: initial
manifestation of cellular immune dysfunction
H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L
Brettman, M Lange, HW Murray, and S Cunningham-Rundles
Barre-Sinoussi et al,
Science 1983
Popovic et al Science,1984
Levy et al Science, 1984
The lymph node in HIV infection is
inflammatory and enriched with effector T
cells
Tenner Racz ‘93
Cheynier ’94
Pantaleo ‘94
Altfeld ‘02
Brenchley ‘04
Biancotto ‘07
Lymph
Node
Naïve T cells
Central
memory
cells
antigen
antigen
Effector cells
See Wednesday
LB: JC Mudd
Homeostatic
proliferation
Peripheral
tissues
Increased fibrosis in the
HIV+lymph node
Predicts failure of CD4 T cell
restoration on HAART
Schacker AIDS ‘05
Impairs intercellular
communication
Zeng et al, JCI ‘11
Estes, Schacker and Haase
CD4 T cell homeostasis is broadly
impaired in HIV infection
Lymph Node
Naïve T cells
Central
memory
cell
antigen
antigen
Thymus
Effector cell
Bone Marrow
Homeostatic proliferation
(IL-7 dependent)
Periphery
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
An outbreak of community-acquired Pneumocystis carinii pneumonia: initial
manifestation of cellular immune dysfunction
H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L
Brettman, M Lange, HW Murray, and S Cunningham-Rundles
T10 = CD38
Immune activation predicts HIV
disease progression
Janice Giorgi
• Immune activation predicts HIV
disease progression
– CD38 – a better predictor of disease
progression than VL. (Liu JAIDS ’98, Giorgi JID ’99,
Deeks ’04, Wilson ‘04)
High turnover of both CD4 and CD8 T
cells in HIV infection is attenuated by
antiviral therapy
Kovacs et al J Exp Med ‘01
So if immune activation drives HIV
pathogenesis (CD4 depletion),what drives
immune activation?
• A homeostatic response to cytopenia? (Srinivasula et al ‘11)
• HIV itself?
– Via antigen specific T cell activation and expansion?
– Via products such as envelope that bind and activate
cellular coreceptors? (Herbeuval et al ‘05)
– Via viral elements that activate innate immune receptors?
(Heil et al ‘04, Fontaneau et al ’04, Meier et al ‘07)
• An immune deficient environment that permits replication of
other microbes (eg CMV, other herpesviruses, HCV) (Lisco et al
‘09, Hunt et al ’11)
HIV infection rapidly depletes gut
effector memory CD4 T cells
HIV-
Veazey ’98; Guadalupe ’03; Mehandru ‘04
Matapallil ‘05
HIV+
Brenchley et al JEM 2004
Plasma LPS levels are increased
in chronic HIV infection
Brenchley et al, Nat Med 06
CD4 T cell increase at 48 weeks
Levels of microbial products correlate
inversely with magnitude of CD4 T cell
restoration on HAART
800
R² = 0.2516
700
600
500
400
300
200
100
0
0
50
100
150
Plasma 16s DNA levels copies/ul
Jiang et al J Inf Dis ‘09
200
Brenchley et al Nat Med ‘06
HIV disease is characterized by heightened
inflammation and coagulation
• The environment in both blood and lymph nodes is
inflammatory (Pantaleo ‘94, Andersson ‘00, Biancotto ‘07, Kalayjian ‘10)
• Indices of inflammation (IL-6, CRP) and coagulation (ddimers) predict all cause mortality (Kuller ‘08)
• Activated CD4 T cells show signatures of high level type 1
interferon exposure (Sedhagat ‘08)
And Immune Cells show signs of exhaustion and
senescence
• Increased expression of CD57, PD-1, shortened
telomeres (Vanham ‘90; Effros ’96; Trautmann ‘06, Day ‘06; Petrovas ‘06)
A model of immune activation and
pathogenesis in the HIV+ lymph node
E
CM
CM
CM
E
E
M
APC
Naive
Naive
E
APC
E
E
E
Naive
CM
Naive
APC
E
CM
CM
E
CM
Even after > 5 yrs of HAART and current VL BLD,
~20% of adult pts have CD4 T cell counts below
2, 740
350 the defined normal range
Normal (95%) range
15%
Valid N
Median
Percentile 25
Percentile 75
Percentile 2.5
Percentile 97.5
Minimum
Maximum
Perc ent
10%
>5 years
340
609
412
802
122.525
1417.88
48
1822
5%
0%
100
200
300
400
500
600
700
800
900 1000 1100 1200 1300 1400 1500 1600 1700 1800
CD4
Rodriguez, Myerson
Despite “complete” virologic control on
ARVs, immune failure patients have
increased T cell activation
–
–
–
–
–
–
–
–
–
–
Teixiera AIDS ’01: age and low thymic output
Anthony JAIDS ’03: immune activation and turnover
Benveniste JID ‘05: Low thymic output
Fernandez Clin Imm ‘06: immune activation and senescence
Gandhi JAIDS ‘06: women restore better
Hunt JID ‘08 Immune activation and microbial translocation
Marchetti AIDS ‘08: immune activation and microbial translocation
Rajasuriar JID ‘10: Linkage to IL-7Ra haplotype
Sandler et al JID (in press) immune activation and microbia
Gazzola CID ‘09: Excellent review of immune failure
Fernandez ’06; Hunt ‘08; Marchetti ‘08; Sandler ’11; Lederman ‘11
Though both CD4 and CD8 T cells are
activated in Immune Failure, cell cycling is
increased only among CD4 T cells
_____P<0.001_____________
__P<0.001___
Increased inflammation, coagulation and evidence of
monocyte activation in immune failure despite virologic
control
____p < 0.09_____
What we know
• HIV is the cause of AIDS
• HIV linked to immune
activation; plausible drivers
of activation identified
• Immune activation is linked
to disease course
• Inflammatory cytokine
levels are increased
What we don’t know
• Exactly how HIV causes AIDS
• Which “drivers” are most
important in which setting
• Causality likely; proof lacking
• Which cytokines mediate
pathogenesis; which are just
markers of infection?
• Will blocking these pathways
block activation?
• Will blocking these pathways
alter disease course?
• To what degree and at what
point are these pathways
reversible?
Immune Failure despite virologic control
What we know
What we don’t know
• Increased T cell
activation; increased CD4
T cell cycling
• How much T cell
activation is “push” and
how much is “pull”?
– And among plausible
“pushers” which pathways
are most important?
• Increased coagulation
and inflammation
• What is the link between
T cell activation and
inflammation/coagulation
• The degree to which
“drivers” and mediators
of morbidity in immune
failure are linked to the
drivers of pathogenesis in
untreated HIV infection?
A Way Forward
• Interventional Trials targeting key
pathways of “activation” can concurrently
test hypotheses of pathogenesis and also
explore promising treatment strategies for
persons at risk for morbidity
Thanks
to:
CWRU:
Scott Sieg
Benigno Rodriguez
JC Mudd
Nick Funderburg
Brian Clagett
Len Calabrese
Carey Shive
Wei Jiang
VGTI:
Rafick Sekaly
Elias Haddad
Nicolas Chomont
Lydie Trautmann
Rush:
Alan Landay
NIH
Jason Brenchley
Danny Douek
Netanya Sandler
Mary Carrington
Leonid Margolis
Irini Sereti
Jake Estes
Emory
Guido Silvestri
Mirko Paiardini
Drexel
Jeffrey Jacobson
U. Minnesota
Tim Schacker
UCSF:
Steven Deeks
Peter Hunt
Hiroyu Hatano
U. Penn
Mike Betts
U. Paris
Yves Levy