Download Immune activation and Immunopathology of the HIV infection

New concepts in HIV Immunology
Pr Brigitte AUTRAN
Lab. Immunité et Infections, INSERM U945
Institut Fédératif de Recherches Immunité-Cancer-Infection
Hôpital Pitié-Salpétrière
Université Pierre et Marie Curie, Paris
[email protected]
B Autran EACS 10
1981 - 1997 - 2007 : AIDS and Immune Deficiencies :
• The (only?) Complication of the HIV infection,
• occurring despite strong immune responses to HIV
• Immune Reconstitution with ARV
200
B Autran EACS 09
Infections
Opportunistes
ARV
Réponses Immunes
Cellules CD4/mm3
Charge VIH
SIDA
1997 – 2006: Limitations of ARV :
 Partial restoration of Immunity to HIV
=> Concepts : « auto-vaccination »
by treatment interruption (STI)
CTL
CD4 help
virus
Primo-infection
Infection Chronique:
J Lisziewicz et al. ….E. Rosenberg et al.,
1989, 2000
G Ortiz et al., G. Carcelain et al. B Hirschel et al. …..
1989 ….2002
1998 – 2007 : The « Burial » of the STI concept :
 Lack of viral control after repeated STI
despite rebounds in immune responses
 SMART: Increased Frequency of complications
 HIV-related: opportunistic Infections
 Cardiovascular: HIV-related ????
All serious non-AIDS
Non-AIDS malignancy
Renal
CVD
Liver
Other non-AIDS death
0.2
B Hirschel et al. 2006…..
0.5
1.0 1.5
Adjusted hazard ratio
< 400 vs. > 400 copies/mL
El Sadr et al. 2007
New questions & Novel concepts
in the Immunology of the HIV infection
• Immune activation and Immunopathology of
the HIV infection
• Immune Benefits of Long term antiretroviral
therapy ?
• Immune control of HIV and the dream of HIV
eradication …
B Autran EACS 09
Current issues in HIV immunolgy
• Immune activation and Immunopathology of the HIV
infection: the vicious circle
– What’s new ?
– Current issues:
• Sources of immune activation?
• Consequences of immune activation and cardiovascular alterations
• Markers of immune activation
• Benefits of ART?
• Immune Benefits of Long term antiretroviral therapy
• Immune control of HIV and the dream of HIV eradication ……
B Autran EACS 09
HIV Infection, Immune Activation
and CD4 cell depletion
 CD4 Deficiency negatively correlates to Immune activation
CD4 counts
HIV load
Immune Activation
Immune responses
despite induction of powerful immune responses against HIV
200
 Where is Immune activation coming from ?
B Autran EACS 09
T-cell activation and CD4 count
Hunt, JID 2008
N= 30 HIV+ with VL < 75c/mL
HIV requires immune activation to
replicate in activated CD4 T cells
Antigens
=> HIV replicates
and
In lymphoïd tissues
Cytokines
where
Activation takes place
BAutran/03
Is this new?
No! In 1983 F Barré-Sinoussi et al. discovered
LAV/HIV in a lymph node
1 year before all other groups that looked for HIV in the blood
Science, May 1983, 220, 368
HIV-related apoptosis of the gut mucosal epithelia induces
Microbial translocation
Thus eliciting systemic immune activation
JM. Brenchley, ….AT. Haase,and DC. Douek
Systemic LPS
from translocated
Bacteria correlates
with disease progression
BAutran/06
Nat Med 2006
Systemic LPS binds
Monocytic receptors (CD14)
and elicitsrelease of pro-inflammatory cytokines
What’s new? Chronic Inflammation/activation
plays a key role in immunopathology of HIV
tat,
Appay V et al, J Pathol 08
Inflammation/activation chronique et immunopathologie du VIH
Secretion of Pro-inflammatory
Cytokines
IL-1b, IL-6, TNF-a,….
Chimiokines
MCP-1, CX3CL1, RANTES,….
Inflammation-related Disorders
Atherosclerosis
Osteoporosis
Neurocognitive
Degeneration
= inflamm-ageing ?
from Appay V et al, J Pathol 08
How can HIV induce atherosclerosis?
Through Inflammation and activation of
macrophages
B Autran EACS 09
A Calmy et al & the STACCATO Study Group
et al.
Univariate & multivariate models assessing the association between cardiovascular
markers and HIV RNA at Wk 12 of ART interruption
Inflammation/activation chronique et immunopathologie du VIH
Secretion of Pro-inflammatory
Cytokines
IL-1b, IL-6, TNF-a,….
Chimiokines
MCP-1, CX3CL1, RANTES,….
Inflammation-related Disorders
Atherosclerosis
Osteoporosis
Neurocognitive
Degeneration
= inflamm-ageing ?
from Appay V et al, J Pathol 08
Current issues in HIV immunolgy
• Immune activation and Immunopathology of the HIV infection: the
vicious circle
• Immune Benefits of Long term antiretroviral therapy
– Early effects of ART on Immune activation
– Long Term benefits of ART?
• Can Immune reconstitution continue 10 years after onset of ART?
• Can Long Term ART restore immune defenses?
• Can Long Term ART exhausts the reservoirs of HIV?
• Immune control of HIV and the dream of HIV eradication
B Autran EACS 09
1997: Immune Restoration and Regression of
hyperactivation with ART
Decreased proportions of activated
CD4 and CD8 T cells
Decreased CD38 expression
per CD6 T cells
20
CD8 activés DR+
15
% positive cells
4
HIV
3
10
2
5
1
0
0
2
B Autran 2009
4
6
Mois
8
10
12
14
CD8
CD4 mémoires
activés DR+
Infective cells(log10)/107PBMC
CD4 activés DR+
Immune benefits of 10 years of fully suppressive HAART :
Can CD4 cell recovery continue after 5 years of ART
The Decamune study
CD4 recovery
LTU: Long Term Undetectability
(10 years without Blips at any time:
800
N= 22 out of 800 pts treated for 10yrs)
with median nadir CD4: 212/mm3
between 5 and 10 years
with a 3rd positive
CD4 cell slope
CD4 / mm3
 Sustained CD4 T cell recovery
600
400
200
Decamune
0
0
1
2
3
4
5
6
7
8
9
10
Years of ART
=> Normalisation of CD4 T cell
activation
(Guihot AIDS 2010)
 Normal levels of Activated CD4 T cells (9%
 Persisting low levels of CD8 activation
Current issues in HIV immunology
• Immune activation and Immunopathology of the HIV
infection: the vicious circle
• Immune Benefits of Long term antiretroviral therapy
• Immune Control of the HIV Reservoirs and the dream of
HIV eradication?...
B Autran EACS 09
Maintenance of a long term HIV reservoir in HAART suppressed patients
Estimated lifespan of the
HIV reservoirs:
- 64 years (Finzi et al.)
- 69 years (Chomont et al.)
 No residual replication
= No « internal « re-seeding
of the HIV reservoirs
???
Dynamics of the latent reservoir in viraemic and aviraemic patients
(Siliciano et al. 2007)
G Hutter et al.
The Dream
of HIV eradication
Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….
Reduction of the HIV Reservoirs with a continuous
fully-suppressive ARV?
The Decamune Study (Guihot AIDS 2010) :
Distribution of the HIV Reservoirs in CD4 cells
during ARV N Chomont et al. Nature Medicine 2009
p = 0,05*
p <0,0001*
DNA- copies /106 PBMC
3,000
1,000
600
400
200
0
DNA
cp/MPBMC
(log)
LTU
157
2.2
STU
353
2.5
HIC
30
1.5
 Proviral HIV DNA Predominates in
Low Viral Reservoirs
after 10 years HIV suppression
With ART and continuous CD4 recovery
Central Memory CD4 T cells with 6months ½ lif
 Quasi-undetectable in Naive ly with 10 y lifespan
Emergence of new therapeutic concepts :
From treatment interruption to treatment intensification:
Towards a Functional Cure ?
• To test whether an « add-on »
strategy including :
ARV
Super ARV-intensification
• Immune-Based Therapies targeting:
• Cells actively replicating HIV
HIV DNA
HIV RNA
• ARV super-intensification plus
• Cells latently infected
• Can promote decay or exhaustion of
• residual plasma VL

• HIV reservoirs
Immune Based Interventions

Richman et al. Science 2009, R. Murphy, B. Autran, C Katlama et al. Science 2009
 Can the Immune system help
at controlling the Reservoirs?
IL-7
Purging the HIV reservoirs?
CTLs
Is exhaustion of HIV Immune Reservoirs feasible ?
The Eramune Projects
 Can the most potent combinations of ARV and immune interventions
- That activates « latently » infected cells
- That targets cells actively replicating HIV
 Exhaust the HIV reservoirs ?
Eramune: Study design
cART
Intensification
Optimized
cART
(control)
IL-7
+ Immune
Intervention
Anti_HIV
Vaccines
HIV DNA
HIV RNA
Hyper-ART + Immune
interventions
2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02
Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009
Univ Pierre et Marie Curie Paris-6, CHU Pitié-Salpétrière,
Immunology, INSERM U945
Immunity to viruses
A Samri B Descours
X Jie
V Martinez
A Schnuriger
B M da Silva
W Lu*
G Carcelain
Virology:
H Agut
V Calvez
AG Marcellin
immunogenetics HIV immunosenescence
I Theodorou
V Appay,
J Gueurgnon
J Almeida
Statistics : INSERM U720 C Dalban, D. Costagliola
Clinics: C Katlama, R Tubiana, MA Valantin….
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