towards a therapeutic vaccine to reduce hiv reservoir, both neutralizing hiv and inhibiting effector...
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Towards a therapeutic vaccine to reduce HIV reservoir, both neutralizing HIV and
inhibiting effector T cells depletionPr. Patrice DEBRE
Laboratoire Immunité & InfectionLaboratoire Immunité & InfectionINSERM UMR-S 945INSERM UMR-S 945
Hôpital Pitié-SalpêtrièreHôpital Pitié-SalpêtrièreParis, FranceParis, France
“Towards an HIV Cure” Pre-Conference Symposium20 & 21 July 2012
A strategy to decrease HIV reservoir
INFECTION
Virus Infected CD4 cells
PATHOGENESIS
NK Non-infected
CD4 cells
Vaccine
VirusNeutralizatio
n
Restore Immune-response
An epitope based vaccine, both
1) Inhibiting the deleterious effect of NK cells
A NK ligand on CD4+ T cells ?
2) Neutralizing HIV-1
NKp44L is induced during HIV infection by the 3S/gp41 motif
Kill
NK
CD4
+-NKp44
MHC-I NKp44L
%
NK
p4
4L
010
20
3040
3- 3-4+ 4+8+ 8+
Control PBMCHIV+ PBMC
CD4 / mm3
0 250 500 750 1000010
20
30
40
p=0.002
%
NK
p4
4L
HR1 HR2Fusion Peptide
TM517 532 558 595 643 678
3S motif3S motif
HIV-1 gp41 Env
3S : very conserved motif & specific to HIV-1
NKp44L
2.7% 17.4%
3SUT
CD
4
Vieillard et al Proc Natl Acad Sci USA 2005
gC1qR is the cell-surface receptor of the 3S/gp41 motifon CD4+ T cells
HK
3S
C1q
C3
NA0 25 50 75 100 125 150 175
NKp44L expression (MFI) NKp44L expression
IgMNA
3S
3S+ agC1qR
Role of gC1qR !
Listeria monocytogenesStaphylococcus aureusPlasmodium falciparum
HCV, rubella virus, HSV and HTNV
Fausther-Bovendo et al PLoS Pathogens 2010
Deleterious effect of NK
cells ?
Anti-3S Ab : a predictive value for the evolution of the disease ?
0
100
200
300
0 400 800 1200
Anti-3S (U/mL)
CD4 count/mm3
Vieillard et al AIDS (2006)Unpublished data
Multivariate study between 40 patients (first quartile) with a slope CD4>2.7/month and 40 patients (last quartile) with slope CD4<-6.9/month
Variable Odds-ratio IC95 P
Sexe M WAge (10y)
CD4 (X100)
Log VL
3S Ab (x100)
1.00 1.83 1.30
0.58
1.17
2.89
0.049-6.87
0.76-2.23
0.42-0.81
0.55-2.51
1.60-5.17
0.372
0.334
0.001
0.682
<0.001
Summary-1Summary-1
- NKp44L is specifically expressed on non infected CD4+ T cells from HIV-1 patients;
- NKp44L is induced by a specific peptide from the gp41 HIV-1 protein;
- Anti-3S antibodies are predictive of the disease evolution.
A 3S vaccine inhibiting HIV pathogenesis
1- Macaque model of SHIV infection1- Macaque model of SHIV infection(Vieillard et al, AIDS 2008)(Vieillard et al, AIDS 2008)
2- Prophylactic vaccination2- Prophylactic vaccination(Vieillard et al, PNAS 2008)(Vieillard et al, PNAS 2008)
3- Therapeutic vaccination3- Therapeutic vaccination(Vieillard et al, submitted)(Vieillard et al, submitted)
Proof of concept in macaques
Collaboration: Roger Le Grand (CEA, Fontenay-aux-roses; France)
Prophylactic vaccination by the 3S-gp41 peptideProphylactic vaccination by the 3S-gp41 peptide
Vieillard et al Proc Natl Acad Sci USA (2008)
D385
InfectionSHIV162P3
D0
Immu 1
D30
Imm. 2
D60
Imm. 3
D585
Animal groups :
Analysis:
• Anti-3S antibodies • Plasma viral load• Blood lymphocyte phenotyping• NK & CD4 activation• Cytotoxicity• Apoptose• Inflammation
Sacrifice
Study design
KLH-control macaques :
3S-immunized macaques :
Effect of 3S vaccination on Viral load, NKp44L expression, Effect of 3S vaccination on Viral load, NKp44L expression, and CD4 countand CD4 count
CD
4 /
mm
30
500
1000
1500
2000
0 50 100 150 200
** *
Vir
al lo
ad
1
102
104
106
108
0 50 100 150 200
NS NS
0
1020
30
40
50
0 50 100 150 200
% C
D4
+N
Kp
44
L+
0
500
1000
1500
-400 -200 0 200
an
ti-3
S (
U/m
L)
3S
3S3S SHIV162P3
Days post-infection
KLH-control macaques 3S-immunized macaques
3S
3S
3S
3S
Effect of 3S vaccination on CD4 activation & InflammationEffect of 3S vaccination on CD4 activation & Inflammation
0 20 40 60 80Days post-infection
% C
D4
+C
D6
9+
0
2.5
5
7.5
10
KLH-control macaques 3S-immunized macaques
Days post-infection70
1020304050
CR
P (
g/ml)
**
*
0 210
20
40
60
80
0
TN
F-
(pg/ml)
**
7 21
Summary-2Summary-2
• Immunogenicity in cynomolgus (anti 3S response)
• BUT Unchanged viral load
• Decreased NKp44L expression on CD4+ T cells• Decreased NK cells cytotoxicity on CD4+ T cells• Decreased CD4+ T cells apoptosis• Preservation of CD4+ T cell counts• Decreased immune activation• Decreased inflammation during the acute phase
Summary
Epitope 3S(SWSNKS)
CD4+ T cell
HIV infected cells
HIV virion
gp41
NKp44L
CD4+ T cell lysis
Autologous NK cells
Anti-3S Ab
NKp44
CD4+NKp44L+ cell
E/T ratio
0
10
20
30
40
100/150/125/112.5/1
44L+
44L-
% N
K
Lysis
CD4 depletion
Cell activation
Inflammation
An epitope based vaccine, both
1) Inhibiting the deleterious effect of NK cells
2) Neutralizing HIV-1
Search for an effect of 3S mutant
NH2-SWSNKS-NH2
Alanine scanning
HIV infectivity of 3S mutants
Infectivity
0
25
50
75
100
WT S613A W614A S615A N616A K617A S618A
% p24 production
Entry
%-galactosidase
activity
0
25
50
75
100
WT S613A W614A S615A N616A K617A S618A
Neutralizing effect of anti-3S mutant Abs
200
100
50
150
00 5 10 15 20
Ig (g/ml)
200
100
50
150
0
Human AbsMice Abs
200
100
50
150
00 5 10 15 20
Ig (g/ml)
p24 (ng/ml)
00 4 6 8 10
Days post-infection
2
200
100
50
150
p24 (ng/ml)
WA
WA
WT
WT
WT
WT
W/o Ab
#109
#109
p24 (ng/ml)
0 4 6 8 10
Days post-infection
2
Antibodies against 3S (WA) mutants also inhibit NK pathogenesis
NT 3S WT
#117 #24 #44
#65 #71 #109
NKp44L
68.3 6.4
21.9 34.6 28.4
21.9 31.3 22.7
CD107a
NT 3S WT
38.3 58.2
2.90.6
29.4 34.1
28.67.9
32.1 64.2
2.11.6
#117 #24 #44
30.3 55.1
1.81.8
40.9 52.1
4.92.1
29.9 61.0
7.71.4
#65 #71 #109
NKp44
30.4 62.6
5.91.1
36.4 55.0
6.32.3
34.9 55.4
7.81.9
ConclusionConclusion
1) Restoring/preserving CD4 cell functions
A gp41 epitope based vaccine, both
2) Neutralizing HIV-1
As a tool to decrease HIV reservoir
In Progress …In Progress …
Animal Model Clinical trialPhase I/IIa
HIV-1 infection
Non-infectedAIDS
Asymptomatic phase
TherapeuticVaccine
Antiretroviral Therapy
Unité Immunité & Infection
Team-2
Patrice Debré
Hugues Fausther Bovendo
Caroline Petitdemange
Alexis Sennepin
Abla Achour
Florence Baychelier
Vincent Vieillard
Team-1
Brigitte Autran
Assia Samri
Unité Epidémiologie
CliniqueDominique Costagliola
Service de Virologie
Henri AgutVincent CalvezDaniel CandottiIsabelle Malet
Service des Maladies
Infectieuses & Tropicales
Christine Katlama
Hôpital Pitié-Salpêtrière - Paris
Institut Pasteur
Olivier Schwartz Nathalie Sol-Foulion
Felix Rey
CEA
Laboratoire d’ Immuno-VirologieRoger Le Grand
Nathalie Deudreude-Bosquet
Aurélien Corneau
Isabelle Mangeot-Méderlé
… Grants
ANRS
Sanofi-Pasteur
Bill & Melinda Gates Foundation
Agence Nationale de Recherche (ANR)
InnaVirVax
ORVACS
PartnersPartners
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