Réservoirs VIH : du contrôle à l`éradication

Réservoirs VIH : du contrôle à l'éradication
Asier Sáez-Cirión, PhD
Unité de Régulation des Infections Rétrovirales
HIV-1 life cycle and latency
M. Coiras et al Nat Rev Micro 2009
HIV-1 life cycle and latency
L. Colin et al Retrovirology 2009
- 
The site of integration
- 
The pool of
transcription factors
- 
Chromatin
organization
- 
Tat and tat associated
factors
- 
MicroRNA and RNA
interference
Cell targets, dissemination and sanctuaries
Preferential cell targets of HIV-1:
monocyte/macrophages, DC, α4β7 or
CCR6+ T cells
Spreading of the infection: lymph
nodes, mucosal tissue, gut, brain
Compartmentalization
Nicolas Chomont
Viral replication resumes as soon as therapy is interrupted
Viral reservoirs persist in HIV-infected individuals
receiving cART
Finzi et al. Cells 1997
Palmer et al. J Internal Medicine 2011
Full life expectancy is not restored by HAART
Probability of Survival
1
0.75
Population controls
0.5
HAART (2000-2005)
0.25
HAART (1997-1999)
Pre-HAART (1995-1996)
0
25
30
35
40
45 50 55
Age, years
60
65
70
Danish HIV Cohort study n=3990; HIV neg controls n=379,872"
Lohse et al., Ann Int Med 2007: 146: 87
Targeting viral reservoirs
Limiting è Remission
Draining è Eradication
CLUES for a func?onal cure
What can we learn from HIV controllers? CO18 Study
HIV controllers (HIC): infected individuals
spontaneously controlling HIV-1 infection
HIV infected for more than 10 years, naïve of
antiretroviral treatment, but their plasma viral loads
remain undetectable (~0.5% of HIV-infected patients)
Lambotte O et al, Clin Infect Dis. 2005
80
1600
CD4 T cell counts/µl
1200
1500
1000
800
1000
600
400
500
200
0
0
2000
2002
2004
2006
2008
2010
B35
% of patients
1400
HIV-1 RNA (copies/ml plasma)
2000
60
B27
B57
40
20
0
Non
infected
HIV
infected
HIC
HIC have achieved and extremely weak HIV-1 reservoir
HIV-DNA (log10 copies/106 PBMC)
6
5
4
3
2
1
PRIMO
CHRONIC
HAART
ALT
HIC
Saez-Cirion et al, Blood 2011
An efficient immune response and protective HLA alleles
influence HIV reservoirs
8.5
0.1
13.2
0.1
4.8
1.7
10.1
5.0
HIC
CD8 T cells from HIC have an impressive
capacity to eliminate autologous HIVinfected CD4+ T cells
cd4 Viremic
Saez-Cirion PNAS 2007
p24
Shan et al Immunity 2012
Descours, Avettand-Fenoel et al CID in press
Cellules T CD4
Macrophages
104
p=0.003
3
10
2
10
1
10
100
10-1
HIC
HD
p24 in culture supernatants (ng/ml)
p24 in culture supernatants (ng/ml)
Macrophages and CD4+ T cells from controllers are less
susceptible to HIV infection in vitro
104
103
p<0.00001
102
101
100
10-1
HIC
HD
HIV susceptibility in vitro correlates with the size of viral
reservoir in vivo
Saez-Cirion et al, Blood 2011
Is it possible to induce a HIV controller-like status
from the reservoir point of view?
VISCONTI Study
Some patients are able to control efficiently and durably
their viral loads after treatment interruption
VisORA02
109
2000
108
106
1500
RNA copies/ml
CD4+ T cells/mm3
107
105
104
1000
103
102
500
101
0
01
100
02
03
04
05 06
Year
07
08
09
10
Post-­‐treatment controllers (PTC) These pa?ents ini?ated cART within 10 weeks following PHI 3 years on therapy followed by 6 years of HIV control off therapy A long-term treatment initiated during primary infection
Seems to increase the chances to control viremia
<1 % spontaneous controllers
HIC
Non controleurs
>10% controllers after interruption
of early treatment
CAT
Non controleurs
Virtually no patient treated during the chronic phase of
infections is able to control the viral load after treatment
interruption
CLUES for eradication
The Berlin patient: a case of sterilizing cure?
Bone marrow
transplantation
AML diagnosis
HIV-1 RNA (copy/mL)
HAART
2nd bone marrow
transplantation
HAART
107
106
105
104
103
GI tract biopsy
102
2007
2008
CSF
2010
•  Latently infected cells can be eliminated
•  Anatomical reservoirs can decay
Hutter et al., N Engl J Med, 2009; 360:692
CHALLENGES
1- Limit the establishment of the viral reservoir
2- Efficiently reactivate reservoirs
3- Preserve/potentiate immune responses
Plasma Viral load
Reduced dynamics of viral replication
CTL
Progressor
Preserved T cell response
HIC
Time
Acknowledgements
Institut Pasteur
Unité de Régulation des Infections Rétrovirales
Gianfranco Pancino
Françoise Barré-Sinoussi
Chiraz Hamimi
Anna Bergamaschi
So Youn Shin
CHU Necker Enfants Malades
Laboratoire de Virologie
Annie David
Christine Rouzioux
Pierre Versmisse
Faculté de Médecine Paris Sud
Véronique Avettand-Fenoel
Adeline Mélard
INSERM U1012
Alain Venet
Martine Sinet
Olivier Lambotte
Cécile Goujard
Isabelle Girault
Camille Lecuroux
Aurelia Lamine
INSERM U1018
Laurence Meyer
Christiane Deveau
Faroudy Boufassa
CHR Orléans La Source
Service Maladies Infectieuses
Thierry Prazuck
Laurent Hocqueloux
CHU Hôtel-Dieu
Unité Immuno-Infectiologie
Jean-Paul Viard
For sharing slides
Olivier Rohr
Benjamin Descours
Laurent Hocqueloux
CHU Pitié Salpêtrière
INSERM U543
Ioannis Theodorou
Julien Guergnon
Patients and physicians who participate to this study
ANRS CO18 “HIC”
ANRS VISCONTI
ANRS CO6 “PRIMO”