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New concepts in HIV Immunology
Pr Brigitte AUTRANLab. Immunité et Infections, INSERM U945
Institut Fédératif de Recherches Immunité-Cancer-InfectionHôpital Pitié-Salpétrière
Université Pierre et Marie Curie, [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
B Autran EACS 09
Rép
on
ses
Imm
un
es
Cel
lule
s C
D4/
mm
3C
har
ge
VIH
200
SIDAInfections
Opportunistes
ARV
1997 – 2006: Limitations of ARV : Partial restoration of Immunity to HIV
=> Concepts : « auto-vaccination »
by treatment interruption (STI)
Primo-infectionJ Lisziewicz et al. ….E. Rosenberg et al.,
1989, 2000
CTL CD4 help virus
Infection Chronique: 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 ????
Renal
Liver
All serious non-AIDS
CVD
Non-AIDS malignancy
Other non-AIDS death
Adjusted hazard ratio < 400 vs. > 400 copies/mL
1.0 1.50.50.2
B Hirschel et al. 2006….. El Sadr et al. 2007
New questions & Novel conceptsin 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
Imm
un
e re
spo
nse
sIm
mu
ne
Act
ivat
ion
CD
4 co
un
tsH
IV lo
ad
200
CD4 Deficiency negatively correlates to Immune activation
despite induction of powerful immune responses against HIV
B Autran EACS 09
Where is Immune activation coming from ?
T-cell activation and CD4 count
Hunt, JID 2008 N= 30 HIV+ with VL < 75c/mL
Antigens
and
Cytokines
=> HIV replicates
In lymphoïd tissues
where
Activation takes place
BAutran/03
HIV requires immune activation toreplicate in activated CD4 T cells
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 Nat Med 2006
BAutran/06
Systemic LPS from translocated
Bacteria correlates with disease progression
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
from Appay V et al, J Pathol 08
Secretion of Pro-inflammatory
Cytokines
IL-1, IL-6, TNF-a,….
Chimiokines
MCP-1, CX3CL1, RANTES,….
Inflammation-related DisordersAtherosclerosis
Osteoporosis
Neurocognitive
Degeneration
= inflamm-ageing ?
How can HIV induce atherosclerosis?Through Inflammation and activation of
macrophages
B Autran EACS 09
et al.
Univariate & multivariate models assessing the association between cardiovascular
markers and HIV RNA at Wk 12 of ART interruption
A Calmy et al & the STACCATO Study Group
Inflammation/activation chronique et immunopathologie du VIH
from Appay V et al, J Pathol 08
Secretion of Pro-inflammatory
Cytokines
IL-1, IL-6, TNF-a,….
Chimiokines
MCP-1, CX3CL1, RANTES,….
Inflammation-related DisordersAtherosclerosis
Osteoporosis
Neurocognitive
Degeneration
= inflamm-ageing ?
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
% p
osi
tive
cel
ls
Infe
ctiv
e ce
lls(l
og
10)/
107P
BM
C
0
5
10
15
20
0 2 4 6 8 10 12 14
1
2
3
4
CD4 activés DR+
CD4 mémoiresactivés DR+
CD8 activés DR+
HIV
Mois
Decreased proportions of activated CD4 and CD8 T cells
CD
8
Decreased CD38 expression per CD6 T cells
B Autran 2009
LTU: Long Term Undetectability
(10 years without Blips at any time:
N= 22 out of 800 pts treated for 10yrs)
with median nadir CD4: 212/mm3
Sustained CD4 T cell recovery
between 5 and 10 years
with a 3rd positive
CD4 cell slope
=> Normalisation of CD4 T cell
activation
(Guihot AIDS 2010)
Immune benefits of 10 years of fully suppressive HAART :
Can CD4 cell recovery continue after 5 years of ART
The Decamune study
Years of ART
CD
4 /
mm
3
0
200
400
600
800
1 2 3 4 5 6 7 8 9 100
Decamune
CD4 recovery
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
Dynamics of the latent reservoir in viraemic and aviraemic patients(Siliciano et al. 2007)
No residual replication= No « internal « re-seeding of the HIV reservoirs ???
Estimated lifespan of the HIV reservoirs:- 64 years (Finzi et al.)
- 69 years (Chomont et al.)
Maintenance of a long term HIV reservoir in HAART suppressed patients
Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….
G Hutter et al.
The Dream
of HIV eradication
Reduction of the HIV Reservoirs with a continuous
fully-suppressive ARV?
0
200
400
600
1,000
3,000
LTU STU HIC
DN
A-
co
pie
s /
106
PB
MC
cp/MPBMC 157 353 30
p = 0,05*p <0,0001*
(log) 2.2 2.5 1.5
DNA
The Decamune Study (Guihot AIDS 2010) :
Low Viral Reservoirs after 10 years HIV suppression
With ART and continuous CD4 recovery
Distribution of the HIV Reservoirs in CD4 cells
during ARV N Chomont et al. Nature Medicine 2009
Proviral HIV DNA Predominates in
Central Memory CD4 T cells with 6months ½ life
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-intensification plus
• Immune-Based Therapies targeting:
• Cells actively replicating HIV
• Cells latently infected
• Can promote decay or exhaustion of
• residual plasma VL
• HIV reservoirs
HIV
RN
AH
IV D
NA
ARV
Super ARV-intensification
Immune Based InterventionsRichman et al. Science 2009, R. Murphy, B. Autran, C Katlama et al. Science 2009
Purging the HIV reservoirs?
IL-7
CTLs
Can the Immune system help
at controlling the Reservoirs?
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 ?
Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009
Hyper-ART + Immune interventions
HIV
RN
AH
IV D
NA
OptimizedcART
(control)
OptimizedcART
(control)
cART Intensification
cART Intensification
+ ImmuneIntervention
+ ImmuneIntervention
An
ti_H
IV
Vaccin
es
Eramune: Study design
IL-7
2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02
Univ Pierre et Marie Curie Paris-6, CHU Pitié-Salpétrière,
Immunology, INSERM U945 Immunity to viruses immunogenetics HIV immunosenescence A Samri B Descours I Theodorou V Appay, X Jie V Martinez J Gueurgnon J AlmeidaA Schnuriger B M da SilvaW Lu*G Carcelain
Virology: Statistics : INSERM U720 C Dalban, D. CostagliolaH Agut Clinics: C Katlama, R Tubiana, MA Valantin….V CalvezAG Marcellin
The ORVACS Network