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
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 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 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-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
Immune benefits of long term fully suppressive HAART :
Is Immune Activation completely controlled ?
Immune benefits of long term fully suppressive HAART :
Control of Immune Activation is associated with better
immune status prior to treatment :
TREAT EARLY => BETTER LONG TERM CONTROL OF IMMUNE 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
G Hutter et al.
The Dream
of HIV eradication
Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….
HIV RESERVOIRS at various stages of the HIV infection
Effect of early and long term ART
Data from the french ANRS Cohorts
The Decamune Study
(Guihot AIDS 2010) :
Viral Reservoirs
after 10 years ART
DNA- copies /106 PBMC
p = 0,05*
p <0,0001*
3,000
1,000
600
400
200
0
DNA
cp/MPBMC
(log)
LTU
157
2.2
STU
353
2.5
HIC
30
1.5
Similar results: Chun JID 2011
TREAT VERY EARLY : BEST CONTROL OF THE HIV RESERVOIRS
Critical role of the Long lived CD4 T cells : Central memory T cells
(TCM): required for long term maintenance of the immune functions
A clue for a Therapeutic control of the HIV Reservoirs?
Life span
Naive CD4
TCM
10 Years (?)
(> 3-6 mths)
?
(1-3 mths?)
TEM
Effector
(8-15 days)
Apoptosis
effector
effector
Effector
CD4 T
cells
CCR7
memory
Effector
memory
Memory
CD4 T cells
CCR7
Naive
CD4+cell
Transitional
CD45RA
Distribution of the HIV Reservoirs in CD4
cells during ARV
CD45RA
Central
memory
memory
Memory
CD4 T cells
CCR7
CD45RA
memory
memory
Transitionnal
CD4 T cells
CCR7
CCR7
N Chomont et al. Nature Medicine 2009
Turnover
CD27
CD45RA

 Proviral HIV DNA Predominates in
Memory CD4 T cells with 6months ½ life
 Quasi-undetectable in Naive Ly with 10 y lifespan
 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
Why hav’nt we an HIV vaccine yet?
• A failure but not a lack of researches
• Obstacles against HIV vaccines : HIV escape
– Immediate and definitive HIV Integration in host genome
= Trojan Horse
– HIV Variability in Antibody and T cell epitopes (Enveloppe, Tat, Nef, Gag)
– Weak neutralizing antibodies
Difficulties illustrated by the lack of spontaneous recovery
from the infection
BA ADVAC10
Obstacles to HIV Vaccines: Kinetics of early infection and HIV prevention
A Haase, Nature Reviews Immunology 2010
:
Targets for vaccinal responses to HIV
from
Targets for vaccinal responses to HIV
from
Targets for vaccinal responses to HIV
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