Download HIV – Elite Controllers, LTNPs

Immunology of HIV:
What can we learn from
LTNPs / Elite Controlers ?
Pr Brigitte Autran
Inst. of Researches Immunity, Cancer and Infection ,
Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière,
France
[email protected]
Univ. Hosp Pitié-Salpétrière
HIV and Immune Deficiencies :
• Are CD4 defects & AIDS the only complication of the HIV infection?
• The collateral damages of Immune activation…
CD4/mm3
Pl VL
Opportunistic
Infections
200
0
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3-6 m
8-10 years
ARV
Immune Responses
Immune Activation
AIDS
Chronic Inflammation/activation plays a key
role in immunopathology of HIV
tat,
Appay V et al, J Pathol 08
LTNPs and HIV / Elite Controllers:
Models of functional Cure of HIV?
• Who are they ?
• Definition?
• Control of CD4 and HIV : is it stable ?
• Control of Immune Activation ?
• How do they control the virus ? : Is it the
Virus or the Host ?
• Which virus characteristics ?
• Which Immunity ?
• Are they a model for :
• Vaccines ???
• Cure of HIV ?
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Which definition for
LTNP and HIV / Elite Controllers ?
• LTNPs:
• 1st evidence: 1993: LTS (Long Term Survivors): SanFrancisco Cohort: S Buchbinder & J Levy (1994)
• Immuno/Clinical definition: > 1994: LTNPs:
» Seropositivity > 7-8 years
» No AIDS,
» Normal CD4 counts : >500, >600/mm3
» No Treatment
» (VL not available)
• HIV / Elite Controllers (Suppressors):
• 1st evidences: 2000s:
HIV Controlers: O. Lambotte 2005 / HIV Suppressors: J. Blanke 2005
Elite Controllers : S Deeks & B Walker 2007
• Virological Definition:
 Seropositivity > 8-10 years
 Plasma Viral Load < 400 or 500 cp / mL over 90% measures +/- undetectability
 No Treatment
 (AIDS symptoms or CD4 non necessary)
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Which Epidemiology for
LTNP and HIV / Elite Controllers ?
Data from FHDH:
• LTNPs:
• 1993: LTS SanFrancisco Cohort: 7%? S Buchbinder (1994)
• Others : < 5%, <2%, ….
• HIV / Elite Controllers :
• late 90s: HIV
/ Elite Controlers:
??? < 1%
• French Hospital Data Base (FHDH):
Grabar.. D Costagliola, AIDS 2009
46,880 HIV+ patients:
•
•
LTNP: Sero+ >8y , CD4 nadir > 500
•
Elite LTNP: idem + CD4 nadir > 600, CD4 slope+ = 0.05%
= 40% HIC
= 32% EC
= 60% detectable plVL
•
HIV Controlers: >10y , 90% VL<500cp/ml
= 0.22%
•
Elite Controllers: idem HIC + last VL<50 cp
= 0.15%
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= 0.4%
•
Elite LTNP:
Elite Controlers:
= 46% LTNP
= 12% Elite LTNP
= 25% CD4 < 500/mm3
French Cohort of LTNPs: ALT –ANRS CO15:
• Recruitment: 1994 – 96 :
• Inclusion Criteria :
Seropositivity known > 8 years
CD4>600/mm3 for > 5 years and + CD4 slope
Lack of HIV-related symptoms
Lack of ARV
• N=71:
median seropositivity: 9 y
• Evolution: very slow decrease in CD4 over an 18 years Follow-up:
2000
1800
Years Number subjects Nb CD4>600
1600
1
71
46 (65%)
2
61
28 (46%)
3
44
17 (27%)
CD4/mm3
1400
1200
1000
800
600
4
30
12 (40%)
5
24
8 (33%)
200
18
9 (44%)
0
2001-12
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400
CD4_S0
CD4_S1
CD4_S2
CD4_S3
CD4_S4
HIV – Elite Controllers, LTNPs
• The Virus or the Host?
– Deletions ?
– Evolution and escape ?
– What is the key parameter ?
• Production or Reservoir ?
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HIV characteristics at entry:
It is NOT the Virus !
ALT-ANRS CO15 cohort:
1000000
•
Plasma HIV-RNA (cp/mL)
• Low but Heterogeneous viral production:
Median plasma VL =
•
10 000 cp/mL at entry (20-880,000)
•
Slow increase:
Candotti et al. 1999, 2000
100000
10000
1000
100
• R5-dependent HIV Type:
10
All isolates: NSI (Candotti J Gen Virology1999)
ARNJ0 ARNS1 ARNS2 ARNS3 ARNS4
• No HIV gene deletion in:
env, nef, gag, LTR but a Vif signature (Candotti, Vigne, J Virol 2000)
1000000
 SIMILAR FINDINGS
Viremic
Slow Progressors
100000
in OTHER LTNP COHORTS
• Low Reservoir (cell associated HIV-DNA)
correlated to virus production
Elite
Controlers
10000
HIV RNA
Viremic
Controlers
1000
100
10
1
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1
10
100
1000
HIV DNA
10000
100000
HIV DNA Log copies/106 PBMC
Low HIV Reservoir (HIV-DNA) in PBMC : associated
with a low risk of HIV disease progression
5
4
3
2
1
0
3
2,5
2
1,5
PRIMO Progressors PRIMO
infection
SEROCO
treated
1
LTNP
ANRS Co-15
0,5
0
HIV-controllers
ANRS Co-18
10
S Lewin & C Rouzioux et al. AIDS 2011
HIV / Elite Controllers, LTNPs
Do they control T-cell activation ?
 Low Immune Activation in Elite Controlers with undetectable plVL:
• CD4 activation as low as in ARV-suppressed patients, CD8 activation higher
Hunt, JID 2008
HIV – Elite Controllers, LTNPs
• The Virus or the Host?
– Is it all in the Genes ?
• Immune Response genes
– Adaptive Immunity
– Innate Immunity
– Is it the anti-HIV Immunity ?
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ImmuneGenetics and control of the HIV Reservoirs:
Genome-wide analysis in Elite Controllers and LTNP
 HLA-B57 (HCP5)
is the strongest Marker
for low HIV reservoirs

The HLA locus in Chromosome 6
(Dalmasso et al.)
is the strongest genetic marker for:
• HIV controlers vs Acute infection,(Dalmasso et al.: 2009)
• Elite Controlers (Pereyra et al. 2010)
• LTNP (GISHEAL: French & Italian) vs Acute infection (Guergnon et al:2011)
Lower Reservoir
(HIV-DNA)
in B27+/57+
vs negatives
B Descours et al.
Clin. Inf. Dis 2011
13
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ANRS-CO15 (ALT) cohort:

Immune Genetics of LTNPs :
It is the HOST !
A composite of HLA + chemokine /chemoreceptors gene mutations
CCR5 D32(hzg) + SDF-1 wt + HLA-B27+, DR6-+ 3 of the HLA-A3, B14, B57 + DR7
Significantly predicts 80% of LTNP vs Progressors
(Magierowska et al.Blood, 2000)
•
 Protective HLA
Association HLA-B57 and low pl VL:
5
Median log10 HIV
4
HIV-RNA Cp/mL
enriched during Follow-up:
HIV-DNA Cp/Million
59% at Year0 vs 75% at year5
PBMC
P=0.01
P=0.003
3
 Distinct influences:
HLA-B57 and B14 associated
2
to HIV control
HLA-B27 associated
1
0
to LTNPs
TOTAL
HLA
+- +-
B57 n=19
+- +-
+- +-
B14 n=14
B27 n =14
+- +-
B12
n=13
Antoni G, AIDS 2013
 SIMILAR FINDINGS for HLA-B57 in all LTNP / HIC & EC cohorts
(M Carrington, 1999, Deeks & Walker, 2007, ….)

Other genetic parameters??? Mutations of the KIRDL1 gene (M Carrington 2005), CX3CR1gene (Faure 2001) No gene
polymorphisms in TRIM-5, APOBEC3G, FcgR
 Genome Wide Association Studies (GWAS)
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HIV – Elite Controllers, LTNPs
• The Virus or the Host?
– Is it Immunity ?
• T cell adaptive Immunity:
• CD8 T cells ?
• CD4 T cells ?
Specificity ?
Function ?
Function ?
Other parameters ?
Gene associations ?
Correlates of protection ?
Is it the hen or the egg ???
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The ANRS Co-18 Cohort of HIV Controllers:
CD8 T cells mediate a strong anti-viral activity
104
 CD8 T cells from HIC
inhibit HIV production
p24 (ng/ml)
103
Saez-Cirion, PNAS 2008
2
10
101
CD4 T cells
100
CD4:CD8 1:1
10-1
HIC
Control
VIR
ART
 Some correlation between anti-viral functions
of CD8 T cells from HIC
HIV inhibition and IFN-g production
Saez-Cirion, JI 2009
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IFNg SFC Total /106 PBMC
Mean
16000
Spearman 0.836
14000 p<0.0001
12000
10000
8000
6000
4000
2000
0
0
1
2
3
4
5
p24 log decrease (CD4 vs CD4:CD8 1:1)
LTNP - ANRS-CO15 cohort: Robust HIV-specific CD8 T cells
 Strong CD8 T cells against HIV-Gag :
 CD8 T cells anti-Gag- but not Nef
correlate with low HIV reservoirs
Martinez et al. JID 2005, Jie et al. AIDS 2010
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17
A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs
HLA-B27/57 neg
Inflammation ++
Activation ++
TN
TTM
TCM
Antigens
Antigens
TEM
Antigens
HLA-B27/57pos
TN
TCM
TTM
TEM
HIV Transcriptionally active
HIV Transcriptionally inactive
Anti gag CD8 T cells
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HIV – Elite Controllers, LTNPs
• The Virus or the Host?
– Is it Immunity ?
• Antibodies ?
– Neutralizing ?
– Others ?
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ANRS CO-15 ALT and antibodies against HIV Env
• HIV-specific antibodies: against HIV-enveloppe:
• Neutralizing Abs::
• Positively correlated to the VL:
N’Go et al, AIDS Res Hum Retrov.2003
• Reactivity against the MPER of gp41
Braibant et al. AIDS 2006
2F5-like et 4E10 like Abs in 60% sera
Braibant et al. Virol. 2011
• Reactivity against gp120: particular structural characteristics
VIH
Cell
Membrane
gp4
gp12
1
0
DCSIGN
CD4
CCR5,
CXCR4
• Isotype: IgG2: anti-gp41:
• Best correlate of protection against disease progression
N’Go et al., AIDS Res Hum Retrov. 2003
Martinez et al. J Inf Dis. 2005
• Inhibition of the NK cell-mediated lysis of CD4 T cells: Anti-3S (gp41):
• Debré et al. block NK cell lysis and correlate with disease progression
Vieillard et al. AIDS 2007
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LTNP , HIC and EC: Robust HIV-specific CD4 T cells
r = - 0,304 ;
p= 0,026
Anti-HIV IFNg+ SFC/million
PBMC
10,000
r = - 0,461;
p= 0,0001
10,000
1,000
1,000
100
100
10
10
1
1
1
2
4
6
HIV-1 RNA (log copies / ml)
1
2
3
4
5
Proviral DNA (log cp/106 cell
• LTNPs: Gag-specific Th1 CD4 T cells
• associated with control of HIV & CD4
• The best marker of protection / progression:
in association with anti-gp41 IgG2 Abs
Martinez et al. JID 2005
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Proportion remaining LTNP (CD4>600)
100
80
60
40
P= 0.02
> 170 SFC and IgG2 (n=5)
20
> 170 SFC, No IgG2 (n=11)
< 170 SFC, and IgG2 (n=8)
0
0
< 170 SFC, No IgG2 (n=29)
12
24
36
48
Time from inclusion (months)
60
HIV / Elite Controllers, LTNPs
A model for HIV vaccines ?
• LTNPs, HIC & ECs:
• Strong T cell Immunity to HIV
• Weak Neutralizing Abs but other anti-HIV Abs associated with:
– low VL (IgG2)
– stable CD4 (anti-gp41/3S)
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Are HIV / Elite Controllers, LTNPs
a model for HIV Cure?
Current
AntiRetroVirals
NO AIDS
Persistence of
HIV
Reservoirs
Can we
decrease the HIV
Reservoirs?
and
stop ART?
Functional
Cure ?
or
eradicate HIV
Sterilizing Cure ?
Hot Topic in 2013: Models of Cure ?
Sterilizing cure ?
•
CCR5 defective stem cell graft ( Berlin patient )
Models of Functionnal cure
• Elite Controllers and Long term non progressors
Infected for 10-30 years
Never treated ; Genetic Background;
Strong CD4 and CD8 response/HIV
Preserved central-memory CD4 T cells
Low immune activation
• Post-Treatment Controlers (Visconti)
RNA copies/ml
 Control HIV without ARV for median 3.5 years
OR1
KPV
2000
CD4+ T cells/mm3
-
 After ARV for 5 years started at acute infection
CXK
1500
1000
500
0
96
98
00
02 04
Year
06
08
10 01 02 03 04 05 06 07 08 09 10 11 12 13
Year
OR2
OR8
01 02 03 04 05 06 07 08 09
Year
MWP
 No genetic background; Immunity ???
 Preserved central-memory CD4 T cells
RNA copies/ml
CD4+ T cells/mm3
2000
1500
1000
500
0
01 02 03 04 05 06 07 08 09 10 11 12 13 98 99 00 01 02 03 04 05 06 07 08 09 10
Year
Year
OR3
GXR
02 03 04 05 06 07 08 09 10
Year
JOGA
 Low Immune activation
Hoqueloux et al. AIDS 2010, J Antimicrob. Ther. 2013, Saez-Cirion et al. PLosPathogens, 2013
RNA copies/ml
CD4+ T cells/mm3
2000
1500
1000
500
0
96 98 00 02 04 06 08 10 12
Year
98 99 00 01 02 03 04 05 06 07 08 09
Year
04 05 06 07 08 09 10
Year
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Hot Topic in Sept 2013:
Potential strategies to reduce HIV reservoirs:
Lessons from LTNPs and HIC /ECs
CD8
NKT
APC
Stimulate
Anti-HIV immunity ???
Reduce
Systemic
Inflammation
Immune
Activation
Residual
Replication
HIV Reservoirs
Latency
What can we learn from
LTNPs, HIC & ECs for
Controling Latency ???
EACS B Autran 2013