Diapositive 1

1
"Vers un vaccin contre le SIDA rôle des
cellules NK"
Professeur Patrice DEBRE Laboratoire
dImmunologie Cellulaire et Tissulaire INSERM
U945 Hôpital Pitié-Salpêtrière Paris
2
Pathogenicity
Pathogen
Measles Hépatitis Polio
Rabies
Diphtéria Tétanos Cholera
Vaccines
3
Vaccine
?

• PATHOGENESIS
• CD4 non infected cells
• NK cells

• INFECTION
• virus
• CD4 infected cells

PATHOGENESIS
?
CD4 non infected cells
?
NK cells
4
NKp44L expression by CD4 T cells from
HIV-infected patients
40
p0.002
30
NKp44L
NKp44L
20
10
0
3-
4
8
3-
4
8
0
250
500
1000
750
Control PBMC
HIV PBMC
CD4 / mm3
40
p0.005
30
NKp44L
20
10
0
0.1
10
100
1
1000
viral load(x 1000)
Vieillard et al Proc Natl Acad Sci USA (2005)
5
NKp44L expression is induced by a specific gp41
motif
3S
3S
UT
CD4
2.7
17.4
NK lysis
50/1
25/1
12/1
6/1
E/T ratio
40
30
NKp44L
20
HIV-1 gp41 Env
10
Fusion Peptide
0
HR1
HR2
TM
3S
1
10
20
NH2
517 532
643 678
558 595
anti-3S (mg/ml)
3S motif
3S very conserved motif spécific
to HIV-1
Vieillard et al Proc Natl Acad Sci USA
(2005) Vieillard et al AIDS (2006)
6
Anti-3S Ab a predictive value for the
evolution of the disease ?
Multivariate study between 40 patients (first
quartile) with a slope CD4gt2.7/month and 40
patients (last quartile) with slope
CD4lt-6.9/month
Variable Odds-ratio IC95 p Sexe
0.372 M 1
W 1.83
0.49-6.87 Age (x10y) 1.30 0.76-2.23
0.334 CD4 (x100) 0.58 0.42-0.81
0.001 Log VL 1.17 0.55-2.51
0.682 Anti-3S Ab 2.89 1.6-5.17
lt0.001 (x100)
Vieillard et al AIDS (2006) Unpublished data
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1.3 Anti-3S Ab a predictive value for the
evolution of the disease ?
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Summary-1
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Conclusion-1

• NKp44L is specifically expressed on CD4 T cells
  from HIV-1 patients
• NKp44L is induced par a specific peptide from
  the gp41 HIV-1 protein
• Anti-3S antibodies are predictive of the
  evolution of the disease evolution.

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No expression of NKp44L in CD4 T cells infected
by HIV-1 A new escape mechanism mediated by Nef
NKp44L
HIV-p24
Recombinant vaccinia viruses
VIF
NEF
200
TAT
11.7
60.2
150
72.4
Relative p24NKp44L
100
50
0
100
104
104
101
103
101
103
104
102
100
100
101
102
102
103
NKp44L expression
Fausther Bovendo et al (In press)
HIV viruses
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Effect of Nef mutants on NKp44L expression
12
Effect of Nef mutants on NK cytotoxicity
70
60
50
40
NK lysis
30
20
10
0
100/1
50/1
25/1
12.5/1
E/T ratio
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Conclusion-2

• NKp44L is non-expressed on HIV-infected CD4 T
  cells
• Retention of NKp44L by Nef HIV protein
• However,
• The mechanism of Nef inhibition remains unknown.

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3- Vaccine strategies Macaque model  proof of
concept 
3.1 Macaque model of SHIV infection
3.2 Preventive vaccination
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SHIV162P3-infected macaques model Relationship
between CD4 cell decreases, NKp44L expression and
anti-3S Ab.
Days post-infection
Vieillard et al AIDS (2008)
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Proofs of concept Immunization of macaques by
the 3S peptide
Viral load
CD4 / mm3
Days post-infection
KLH
KLH-3S
Vieillard et al Proc Natl Acad Sci USA (2008)
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Effect of 3S vaccination on CD4 apoptosis, NK
activity et T cell-activation
CD4AnnexinV
NK lysis
Days post-infection
Vieillard et al Proc Natl Acad Sci USA (2008)
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Conclusions
1- Pathophysiology role of NKp44L -
Depletion of non-infected CD4 cells - In
infected cells Escape mechanism by Nef 2-
Immunotherapic interventions - Preventive
vaccine in macaque model, we have
observed - high production of anti-3S Ab
- low expression of NKp44L on CD4 cells.
Stable level of the CD4 cells in
absence of effect on the viral
load !
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Acknowlegments
Pitié-Salpêtrière Hospital, Paris France Laborator
y of Cellular and Tissular Immunology Hugues
Fausther Bovendo Vincent Vieilllard Patrice
Debré Clinical Epidemiology Dominique
Costagliola Department of virology Henry
Agut Daniel Candotti
CEA, Fontenay-aux-roses, France Laboratory of
Immuno-Virology Roger Le Grand Nathalie
Bosquet Pasteur Institute, Paris,
France Department of virology Nathalie
Sole-Foulon Olivier Schwartz Harvard University,
Cambridge, MA Jack Strominger