1. 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
B Autran EACS 10

2. 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
Réponses Immunes
Cellules CD4/mm3
Charge VIH
200
SIDA
Infections
Opportunistes
ARV
B Autran EACS 09

3. 1997 – 2006: Limitations of ARV :
Partial restoration of Immunity to HIV
=> Concepts : « auto-vaccination »
by treatment interruption (STI)
Primo-infection
J 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

4. 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
1.5
0.5
0.2
B Hirschel et al. 2006…..
El Sadr et al. 2007

5. 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

6. 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

7. HIV Infection, Immune Activation and CD4 cell depletion
CD4 Deficiency negatively correlates to Immune activation
despite induction of powerful immune responses against HIV
Immune responses
Immune Activation
CD4 counts
HIV load
200
Where is Immune activation coming from ?
B Autran EACS 09

8. T-cell activation and CD4 count
N= 30 HIV+ with VL < 75c/mL
Hunt, JID 2008

9. HIV requires immune activation to Activation takes place
replicate in activated CD4 T cells
=> HIV replicates
In lymphoïd tissues
where
Activation takes place
Antigens
and
Cytokines
BAutran/03

10. Is this new. No. In 1983 F Barré-Sinoussi et al
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

11. Thus eliciting systemic immune activation
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
Systemic LPS
from translocated
Bacteria correlates
with disease progression
Systemic LPS binds
Monocytic receptors (CD14)
and elicitsrelease of pro-inflammatory cytokines
BAutran/06

12. What’s new? Chronic Inflammation/activation plays a key role in immunopathology of HIV
tat,
Appay V et al, J Pathol 08

13. 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

14. How can HIV induce atherosclerosis
How can HIV induce atherosclerosis? Through Inflammation and activation of macrophages
B Autran EACS 09

15. markers and HIV RNA at Wk 12 of ART interruption
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

16. 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

17. 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

18. 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
% positive cells
Infective cells(log10)/107PBMC 5 10 15 20 2 4 6 8 12 14 1 3
CD4 activés DR+
CD4 mémoires activés DR+
CD8 activés DR+
HIV
Mois
CD8
B Autran 2009

19. 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
CD4 / mm3
200
400
600
800 1 2 3 4 5 6 7 8 9 10
Decamune
CD4 recovery
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)
Normal levels of Activated CD4 T cells (9%)
Persisting low levels of CD8 activation

20. 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

21. 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)

22. The Dream of HIV eradication G Hutter et al.
Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….

23. Reduction of the HIV Reservoirs with a continuous fully-suppressive ARV?
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
200
400
600
1,000
3,000
LTU
STU
HIC
DNA- copies /106 PBMC
cp/MPBMC
p = 0,05*
p <0,0001*
(log)
DNA
The Decamune Study (Guihot AIDS 2010) :
Low Viral Reservoirs
after 10 years HIV suppression
With ART and continuous CD4 recovery

24. 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 RNA
HIV DNA
ARV
Super ARV-intensification
  
Immune Based Interventions
Richman et al. Science 2009, R. Murphy, B. Autran, C Katlama et al. Science 2009

25. Can the Immune system help
at controlling the Reservoirs?
IL-7
Purging the HIV reservoirs?
CTLs

26. 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 ?
Hyper-ART + Immune interventions
HIV RNA
HIV DNA
Optimized
cART
(control)
Intensification
+ Immune
Intervention
Anti_HIV
Vaccines
Eramune: Study design
IL-7
2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02
Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009

27. 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 Almeida
A Schnuriger
B M da Silva
W Lu*
G Carcelain
Virology: Statistics : INSERM U720 C Dalban, D. Costagliola
H Agut Clinics: C Katlama, R Tubiana, MA Valantin….
V Calvez
AG Marcellin
The ORVACS Network