immune reconstitution : quantitative and qualitative aspects · 2015-09-30 · early memory cd4 t...
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Immune Reconstitution :
Quantitative and Qualitative aspects
B.A. Jni07
Pr Brigitte Autran, Hôpital Pitié-Salpétrière, Université Paris -VI
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The 3 phases of the ART-induced immune reconstitution : the 1997-2000 years
1. Early Memory CD4 T cell Redistribution : « Fake » quantitative restoration of CD4 counts but no functionnal restoration
2. Decreased activation with virus control : allows functional restoration3. Late Naive T cell regeneration > long term CD4 T cell quantitative
expansion and Restoration of defenses against OI (Autran 97, Pakker 98, Li 98, Lederman 98, Bucy 98, Gorochov 98….)
Months3 6 9 12 18
CD4
Memory CD4+
Naive CD4+
50
100
0
150
Cel
ls/µ
l
HIV
Activation
B.A. Jni07
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Quantitative and functional CD4 cell reconstitution with HAART
300 patients treated with HAART, viral loads <200 copies/ml
CD4 counts
0
200
400
600
800
0 8 16 24 32Months
Cel
ls/m
m3
Rapid CD4 counts restoration in end stage disease with high risk of CMV retinitis
0
10
20
30
40
50
60
70
0 1 3 6 9 12%
pos
itive
resp
onse
s
CMV Tuberculin
Months
Restoration of proliferative CD4 responses to CMVin end stage disease(Autran 97, Li 98, Lederman 98, Rinaldo 99,
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Similar prognostic significance of CD4 counts during disease and immune reconstitution
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Schematic prediction of Time to restore normal CD4 counts acording to CD4 cell depletion at time of ART initiation
(B Autran et al. 1998)
BA/11.98
8 years4
600
200
CD
4 co
unts
Normal1-22 - 3
5 - 67 - 10
> 10
2 4 6 8 10
6 - 84 - 5
HAART
Factors influencing quantitative CD4 T cell reconstitution:• Positively: - amplitude of HIV control at initiation of ART
- rapid CD4 decrease before ART initiation (Renaud et al, 1999)
• Negatively: - outbreaks of virus replication (blips, STI) (Bategay, 2006)
- HCV co-infections (Koziel 2007)
- X4 virus tropism for naive CD4 T cells (Delobel, 2006)BA JNI2007
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Schematic prediction of Time to restore normal CD4 counts acording to CD4 cell depletion at time of ART initiation :
Where are we today ?
BA/11.98
8 years4
600
200
CD
4 co
unts
Normal1-22 - 3
5 - 67 - 10
> 10
2 4 6 8 10
6 - 84 - 5
HAART
BA JNI2007
Do drugs influence the quantitative CD4 T cell reconstitution:• Similar Immune restoration with PI sparing and PI
containing regimens (INITIO)(Samri et al. Antiviral Ther. 2007)
• Do new drugs generate a distinct profile of immune restoration ???• entry inhibitors ?• integrase inhibitors ?
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Restoration of Immune Defenses against pathogens with ART
Restore defenses to all pathogens (Autran97; Li98, Lederman 98, Rinaldo 99,
Garcia 99, Pontesili99……
Allow arrest of prophylaxis against Opport. Inf (Furrer,99 Reiss 99,Ledereberger 01, Jouan 01..)
Months
50
100
0
150
Opp
ortu
nist
ic P
atho
gens
5
4
3
2
Plas
ma
HIV
RN
A
Memory Cells/ Opportunistic Pathogens
3 6 12 24 48
Naive Cells / Any Pathogens
B.A. Jni07
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Recovery of Memory CD4+ T cell reactivity to CMV allows control of CMV viremia with HAART
1
10
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Months
Sti
mu
lati
on
ind
ex
anti
-CM
V
2
3
4
5
HIV
RN
A (
log
co
pie
s/m
l)
CMV viremia
HIV viral load
CD4 counts
Stimulation index anti-CMV
Positive CMV viremia
21
206
230
Li et al. AIDS Res. Retrov., 99
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Restoration of a CMV-specific T cell reactivity with HAART allows to withdraw prophylaxis against
CMV retinitis in advanced disease
0
20
40
60
80
100
0 4 8 12 16 20Months
% re
spon
ses
to C
MV
0
100
200
300
400
med
ian
CD
4/m
m3
HAART
CMV prevention
47 patients:
Withprior CMV retinitis,
2 relapses after arrest of anti-CMV therapy, Jouan et al, AIDS, 2001
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• Benefits from HAART: => Restoration of CD8 T cell-mediated Immune protection
against CMV retinitis:
=> Comparison of the CMV-specific CD8 T cell magnitude, repertoire breadth and differentiation in:
HN: Healthy HIV- (n=11)LTNP : HIV+HCMV+ Long Term Non Progressors (n=10), med CD4: 733/mm3
HIV+ Recovering from CMV retinitis on ART, after stopping GCV :- Short Term Recovery (18 months, n=8) : CD4:357/mm3- Long Term Recovery (>50 months, n=6) :, med CD4: 345/mm3
Acute CMV retinitis : (n=8) : med CD4:50/mm3K Sacre et al. J Exp Med 2005
Restoration of T cell-mediated immune protection against CMV disease
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Short Term Recovery of strong responses against the CMV early IE1 antigens after CMV retinitis
HCMV-specific SFC/million PBMC per subject
HN LTNP STRR LTRR AHCMV
0
2000
4000
6000
8000
10000
pp65
p=0.02
0
2000
4000
6000
8000
IE1
K Sacre et al, J Exp Med 2005
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HealthyCMV+
HIV-negative
HIV infectionHealthy
CMV +CMV
retinitis
Recovery from CMV retinitis
EARLY LATE
Magnitudeof HCMV-specific CD8 T cells
per target antigen
CD4 counts
Repertoire & diversity of CMV-specific CD8 T cells
against pp-65 IE1
Differentiationof HCMV-specific CD8 T cells
% CD27-28-% CD27-/+28+% CD27+28+
Naive
CMV Replication(detection threshold)
Sacre et al. , JEM 2005
Restoration of Immune Protection against CMV retinitis in HAART treated patients
HAART
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Sequential Restoration of Immune protection against opportunistic pathogens
• CMV retinitis:– Loss of CD4 responses to HIV => Limited repertoire & diversity of short-
lived anti-CMV CD8 T cells => Loss of CMV control– Gancyclovir: control of CMV replication
BUT no restoration of immunity to CMV
• HAART:– Controls HIV =>Restores CD4 counts
• Restores protective Immunity against CMV:– CD4 responses to CMV– CD8 cells to CMV –IE1 antigens
» Large breadth and diversity» long-lived memory CD8 T cells
=> Restores Long Term control of CMV without gancyclovirB.A. Jni07
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Reduction in morbidity / mortality (Hogg, 97, Pallella,98…
Discontinuation of prophylaxis against Opportunistic Infections: PCC. Pneumoniae, CMV retinitis (Furrer,99, Jouan 2001…)
at all stages of the disease : illustrating the lack of definitive immune alterations
BUT Induces the Immune Restoration Syndrome (IRS,.)M French , 98, 2006, Monsuez 99, Breton 2005……….
- during opportunistic infections concommitantly treated with HAART
- reactivation of pathogen-associated symptoms +/- systemic inflamatory
syndrome without microbiological relapse, or of auto-immune diseases
- particularly frequent during mycobacterial infections (MAI, TB : 40%)B.Autran, BA, 01
Rapid restoration of protective memory responses against opportunistic pathogens with HAART
B.A. Jni07
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TB and VIH
IFNγ
CD4 CD4-/8-CD8 TgdTNFα
Disparition of Ag-specific responses,
= Anergy to TB antigens
Consequences of CD4 defects in HIV infection:Poor Granuloma, without caseum, poorly functionalsDisseminated pauci-symptomatic Tuberculosis
Activation macrophage
Activation CD4 Th1
IFNγIL12
• Diminution Nb activated macrophages• Diminution of intra-cellular BK lysis
A. Bourgarit 05
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IRS: Hypothesis
Activation macrophage
Activation CD4 Th1
IFNγIL12
IFNγ
CD4 CD4-/8-CD8 TgdTNFα
Rapid restoration of TB Ag- spécific Th1 cells???
Rapid Restoration of CD4 counts and function with HAART=> Amplification +++ of the specific CD4 Th1 cells to Mtb => inflammatory Syndrome « cytokine Storm »
A. Bourgarit 05
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TBK M0ART M1ART
M3
M6 M12BK
ConfirmationOf inclusion Declaration IRS+
TSRP TSRP+20j
Declaration IRS -
BK+ SRP
ØSRP
ANRS EP-21: PARADOX-TB:A prospective analysis of the Immunological
characteristics of the TB-associated IRS
Bourgarit et al. AIDS, 2006
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IRS+ IRS- pn 11 13M/F 6/5 9/2 NSAge 38 (30-56) 36 (26-63) NSPulmonary TB 2/11 4/13 NSDisseminated TB 9/11 9/13 NS
BAAR+ 3/8 4/13 NSHIV Infection CD4 (/mm3) 26 (6-145) 54 (15-267) NS
CV (Log) 6 (4.8-6.5) 5.2 (4.3-8) NS
M0HAART Délai /TBK (j) 36 (7-77) 50 (14-111) NS
IRS Délai / M0 (j) 23 (7-85)CD4 108 (59-430) 163 (9-580)(M1) NS∆CD4 /M0 (/mm3) +54 (-1;+393) +77 (-50;+250) NS
M3 CD4 117 (58-399) 132 (49-410) NS∆CD4 /M0 (/mm3) +86 (-74;+367) +73 (-88;+354) NSCV <200 7/10 8/11 NS
ANRS EP-21: PARADOX-TB : Patients Characteristics
Bourgarit et al. AIDS, 2006
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TB-IRS: Acute Exacerbation of a Th1 response to tuberculin but not to live TB (ELISpot IFN-γ) (Bourgarit, AIDS 2006)
IRS+n=11
IRS-n=13
PPD : p =0.005
CMV = NS
T BK M 0 M1 M 3 M6 M120
1000
2000
3000
4000
T BK M 0 T IRS M 3 M 6 M120
1000
2000
3000
4000 PPD CMV
SFC/
106 PB
MC
• N IFN-g producing T cells to PPD significantly stronger in IRS +• No or weak response to to live TB-associated antigens: ESAT-6, CFP-10, 85B• Mediated by CD4 T cells: up to 35% of circulating CD4 T cells
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Multiplex Detection of cytokines –Chemokines in culture supernatants (Chimioluminescence)
=> Intense inflammatory response both Ag-specific (PPD) and non specific: cytokines :TNF-a, IL-6, IL-10
chemokines: RANTES, MCP1..
-10 0 10 20 30 40 500
1000
2000
3000
4000 Medium alone CMV PPD
wks
0
10000
20000
30000
40000
50000
IL-6
pg/
ml
TNF-
α an
d IL
-1β
pg/m
l
-10 0 10 20 30 40 500
1000
2000
3000
4000 Medium alone CMV PPD
wks
0
10000
20000
30000
40000
50000
TNF-
α an
d IL
-1β
pg/m
l
IL-6
pg/
ml
IRS+ IRS-
ANRS EP-21: PARADOX-TB :Non PPD-specific pro-inflammatory cytokine storm during IRS
Bourgarit et al. AIDS, 2006
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Paradox-TB: A prospective study of the Immune Restoration Syndrome
associated with TB in HIV infection• A frequent syndrome :
– in 40% (9/22) TB-HIV co-infected patients with severe CD4 defects and rapid CD4 restoration within 3 months after treatment initiation
• A brutal explosion of tuberculin-specific T cells– Poorly or undetectable at baseline, – Rapidly restored and exacerbated, within a month– Mediated by activated CD4 Th1 cells + γδ T cells– with specific release of Th1 cytokines and pro-Th1 chemokines
but without deregulated Th2 response– Directed against Antigens present in tuberculin – Associated to an acute non-specific inflammatory response
Bourgarit et al. AIDS, 2006
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• Paradox-TB : Pending Questions > BK-VIR-IS– Clonality of the response?– Antigens involved? And role of γ-δ T cells?– Role of regulatory T cells ?– Individual susceptibility?
• Why only 40% IRs if this corresponds to a physiological restoration of tuberculin specific T cells?
– Strains ?– Host Genetic Predisposition?
» HLA» Other Genes: Th1 pathways…,
Immune Restoration Syndrome associated with TB in HIV infection
Bourgarit et al. AIDS, 2006
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ANRS and Sidaction PARADOX TB Study group :
Baakili A, Béglé A-M, Besse F, Bollens D, Bouchaud O, Bursachi P, Cadranel J, Camuset J, Chakvetadze C, Delgado J, Diemer M , Dupont B, Elmarsafy S, Fain O, Fonquernie L, Furco A, Girard P-M, Grillot-Courvalin C, Guignet A, Guilleminot MC, Herrmann J-L, Jeantils V, Grivois JF, Joly V, Jouis V, Klutse P, Lacombe K, Lahoulou R, Lavolé A, Lefebvre B, Lefort A, Letellier E, Lortholary O, Metro A TrumeauM, Meynard J-L, Meyohas M-C, Molina J-M, Obenga G , Parrinello M, Pelet O, Pintado C, Ponscarme D, Rami A, Rozenbaum W, Sahli H, Sellier P, Slama L, Courtial S, Tubiana R, Stirnemann J, Tassi S , Taulera O, Touitou H , Vacher I,., Vincent F, Yeni P
Hôpital Saint Louis, Paris FranceIntern. Med.: A Bourgarit, C. Lascoux, D SereniBactériologie: P LagrangeStatistics: V Delcey Institut Pasteur: B Gicquel
Pitié-Salpétrière, Hospital, Immunology : A Bourgarit, G. Carcelain, V Martinez, A. Samri, B. Autran
CHU Pitié-Salpétrière, Univ Pierre et Marie Curie Paris, Immunology, INSERM U543 Infect. Dis. VirologyG. Carcelain, A Samri R. Tubiana V. CalvezB Combadière K Sacre M Jouan AM FilletB. Autran H. Ait Mohand AG Marcellin
C. Katlama H. Agut Statistics : C Dalban, D. Costagliola
and the RESTIMOP study groupANRS , Sidaction and INSERM ATC Immunité anti-virale