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Contribution of the immune
system to HIV persistence
Sharon R Lewin
Director, Infectious Disease Unit, Alfred Hospital
Professor, Department of Medicine, Monash University
Co-head, Centre for Virology, Burnet Institute,
Melbourne, Australia
Towards an HIV Cure, 5th IAS Conference, Rome, 2011
Outline
 Establishing HIV latency
– Where and how are resting T-cells infected?
– Chemokines
– Dendritic cells
 Maintaining HIV latency
– Homeostatic proliferation
– Inflammation
 Role of the adaptive immune response
 Relevance to strategies for cure
establishing HIV
latency
Latent infection can be established
in many T cells
Bone marrow
Thymus
Peripheral circulation
Ag
M M
M M
Naive
Multipotent
progenitor cells
Naïve T cells
Effector/
transitional
Transitional memory
Central
memory
Central memory
Latent reservoir
Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Brooks et al., Nat Med 2001; 7:459 ;
Chomont et al., Nat Med 2009; 15: 893; Dai et al., J Virol 2009: 83(9):4528-37; Carter et al., Nat Med 2010; 16: 446;
Wightman et al., J Infect Dis 2010; 202(11):1738-48
Contribution (%) to the HIV reservoir size
The main reservoir is central and
transitional memory T-cells
100
80
60
40
20
0
TN
CD45RA
CCR7
CD27
+
+
+
TCM
TTM
TEM
TTD
+
+
+
-
+
-
Chomont et al., Nature Med 2009;15: 893
GI tract is enriched for latently infected
cells
Copies per million cells
HIV DNA
N=8, time on HAART with undetectable HIV RNA 2.8 – 12 years
Chun et al., J Infect Dis 2008; 197:714; Yukl et al., J Infect Dis 2010; 202(10):1553-6
Most latently infected and productively
infected cells are in lymphoid tissue
Mmu 35389
VL=17
CSF VL<50
DNA
Lymphoid
tissue
++++
++
++
+
Neg/+
Neg
Reproductive
tissue
+
Neg
Other
+
Neg
GI tract
CNS
RT-SHIV infection
HAART =Tenofovir/emtricitabine/efavirenz
RNA
North et al., J Virol 2010; 84(6):2913-22
Size of HIV Reservoir correlates with
activated CD8+ T cells (in Sigmoid Colon)
Seth et al., Mucosal Immunology 2008:1:382-388
What is unique about these tissue
sites?
 Ongoing replication due to
– Poor penetration of drugs?
– Localised sites of inflammation?
 Unique long-lived cells such as
macrophages or DCs allowing for cell-cell
transmission?
 Infection of resting cells?
Infection of resting T-cells in vitro
Unactivated
resting cells
Resting CD4+ T-cell
In vitro
Ex vivo tissue blocks
chemokines
Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865;
Saleh et al., Blood 2007; 110:416; Cameron et al., Proc Natl Acad Sci 2010 epub Sept 18
Multiple chemokines can induce latent
HIV infection in resting CD4+ T cells.
Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934-9
Chemokine receptor ligation activates
cofilin and actin polymerisation
CXCR4 + gp120
CCR7 + CCL19
Yoder et al Cell 2008
Cameron et al PNAS 2010
Chemokine signalling pathways PI3K
PI3K
SC-514
Bay 11-7082
NFB
NFB
JNK
ERK
P38
Inhibition of Erk1/2, Jnk and NF-kB
eliminates integration (ALu-LTR)
SP600125
PD980509
SB203580
Saleh et al., 5th IAS Conference, Rome, 2011
Infection of resting T-cells in vitro
Unactivated
resting cells
Resting CD4+ T-cell
In vitro
Ex vivo tissue blocks
chemokines
Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865;
Dendritic cells
Saleh et al., Blood 2007; 110:416; Cameron et al., Proc Natl Acad Sci 2010 epub Sept 18
Dendritic cells facilitate latent HIV
infection
Evans et al., unpublished
maintenance of
HIV latency
What is the fate of a latently infected
cell?
Negative
regulators
activation
EM
differentiation
Homeostatic
proliferation
Number of latently infected cells is
correlated with proliferation: role of IL-7
Chomont et al., Nat Med 2009
IL-7 increases proliferation leading to
expansion of HIV DNA in vivo
HIV infected subjects under suppressive HAART received IL-7 injections (ACTG5214,
blind study).
p=0.03
2000
800
1500
600
1000
400
500
200
0
0
Day 0
Day 28
Day 0
Day 28
Vandergreeten 6th IAS conference on HIV Pathogenesis, Treatment and Prevention, Rome, 2011
What is the fate of a latently infected
cell?
Negative
regulators
activation
EM
differentiation
Homeostatic
proliferation
PD-1 hi cells are enriched for latentlly
infected cells
Mock
a-PD-1 blocking Ab
Isotype control
p24 (pg/mL)
Integrated HIV DNA
copies per 106 CD4 T cells
600
400
200
0
Donor A
Chomont et al., Nature Med 2009;15: 893
Donor B
Donor C
Da Fonesca et al., HIV Reservoir Workshop, Vienna, July 2010
What is the fate of a latently infected
cell?
Negative
regulators
activation
IL-15
EM
differentiation
Homeostatic
proliferation
role of the adaptive
immune response
Inverse relationship between HIVspecific CD4+ T-cells and HIV DNA
N=66; long term non progressors, no ARV
Martinez et al., J Infect Dis 2001; 191:2053–63
HLA type influences size and
distribution of latently infected cells
HLA-B27/B57
non HLA-B27/B57
103
102
101
0.0313
TEM
TTM
TCM
TN
TEM
TTM
TCM
p=0.0081
TN
cell HIV-DNA (copies
/millions cells)
104
0.0078
0.0078
0.0078
0.0469
Descours; Avettand-Fenoel Submitted
Summary
 Latency can be established in multiple T-cell
subsets
 High concentration of latently infected cells in
tissue including GI tract and lymphoid tissue
 Chemokines and dendritic cells play a key role
in establishing latency in resting T-cells
 Maintenance of latency can occur by
– Homeostatic proliferation (IL-7)
– Negative regulators of T-cell activation (PD1)
 Adaptive immune response likely important
What is the fate of a latently infected
cell?
Anti-PD-1
Negative
regulators
minocycline
activation
vaccination
EM
Chemokine
antagonists
differentiation
Auranofin
IL-15
Homeostatic
proliferation
Anti-IL7
Acknowledgements

Department of
Medicine, Monash
University, Melbourne
–
–
–
–
–
–
–
Paul Cameron
Suha Saleh
Vanessa Evans
Nitasha Kumar
Ajantha Solomon
Georgina Sallman
Fiona Wightman



Westmead Millenium
Research Institute, Sydney
– Tony Cunningham
– Andrew Harman
VGTI Florida, Port St Lucie,
FL
–
–
–
–
Rafick Sekaly
Elias Haddad
Genevieve Boucher
Nicolas Chomont
Hopital Pitie Salpatriere,
Paris
– Brigitte Autran
– Benjamin Descours