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
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…
B Autran EACS 09
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AIDS Opportunistic
Infections
ARV
0 3-6 m 8-10 years
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 ? EACS B Autran 2013
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)
EACS B Autran 2013
Which Epidemiology for
LTNP and HIV / Elite Controllers ?
• 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 = 0.4%
• Elite LTNP: idem + CD4 nadir > 600, CD4 slope+ = 0.05%
• HIV Controlers: >10y , 90% VL<500cp/ml = 0.22%
• Elite Controllers: idem HIC + last VL<50 cp = 0.15%
EACS: B Autran 2013
Data from FHDH:
• Elite LTNP: = 40% HIC
= 32% EC
= 60% detectable plVL
• Elite Controlers: = 46% LTNP
= 12% Elite LTNP
= 25% CD4 < 500/mm3
• 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:
French Cohort of LTNPs: ALT –ANRS CO15:
Nb CD4>600 Number subjects Years
9 (44%) 18 2001-12
8 (33%) 24 5
12 (40%) 30 4
17 (27%) 44 3
28 (46%) 61 2
46 (65%) 71 1
0
200
400
600
800
1000
1200
1400
1600
1800
2000
CD4_S0 CD4_S1 CD4_S2 CD4_S3 CD4_S4
CD
4/m
m3
EACS B Autran 2013
HIV – Elite Controllers, LTNPs
• The Virus or the Host?
– Deletions ?
– Evolution and escape ?
– What is the key parameter ?
• Production or Reservoir ?
EACS B Autran 2013
ALT-ANRS CO15 cohort: HIV characteristics at entry:
It is NOT the Virus !
• Low but Heterogeneous viral production:
• Median plasma VL =
• 10 000 cp/mL at entry (20-880,000)
• Slow increase:
Candotti et al. 1999, 2000
• R5-dependent HIV Type:
All isolates: NSI (Candotti J Gen Virology1999)
• No HIV gene deletion in:
env, nef, gag, LTR but a Vif signature (Candotti, Vigne, J Virol 2000)
SIMILAR FINDINGS
in OTHER LTNP COHORTS
B.A.EACS 2013
• Low Reservoir (cell associated HIV-DNA)
correlated to virus production 1
10
100
1000
10000
100000
1000000
1 10 100 1000 10000 100000
HIV DNA
HIV
RN
A
Elite
Controlers
Viremic
Controlers
Viremic
Slow Progressors
10
100
1000
10000
100000
1000000
ARNJ0 ARNS1 ARNS2 ARNS3 ARNS4
Pla
sm
a H
IV-R
NA
(cp
/mL
)
10
0
1
2
3
4
5
00,511,522,53
HIV
DN
A L
og
co
pie
s/1
06 P
BM
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PRIMO Progressors PRIMO LTNP HIV-controllers
infection SEROCO treated ANRS Co-15 ANRS Co-18
Low HIV Reservoir (HIV-DNA) in PBMC : associated
with a low risk of HIV disease progression
S Lewin & C Rouzioux et al. AIDS 2011
HIV / Elite Controllers, LTNPs
Do they control T-cell activation ?
Hunt, JID 2008
Low Immune Activation in Elite Controlers with undetectable plVL:
• CD4 activation as low as in ARV-suppressed patients, CD8 activation higher
• The Virus or the Host?
– Is it all in the Genes ?
• Immune Response genes
– Adaptive Immunity
– Innate Immunity
– Is it the anti-HIV Immunity ?
HIV – Elite Controllers, LTNPs
EACS B Autran 2013
ImmuneGenetics and control of the HIV Reservoirs: Genome-wide analysis in Elite Controllers and LTNP
13
The HLA locus in Chromosome 6
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)
HLA-B57 (HCP5)
is the strongest Marker
for low HIV reservoirs
(Dalmasso et al.) Lower Reservoir
(HIV-DNA)
in B27+/57+
vs negatives B Descours et al. Clin. Inf. Dis 2011
EACS B Autran 2013
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)
• Association HLA-B57 and low pl VL:
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)
0
1
2
3
4
5
TOTAL
HLA B57 n=19 B27 n =14 B14 n=14
Me
dia
n lo
g1
0 H
IV
HIV-RNA Cp/mL
HIV-DNA Cp/Million
PBMC
+ - + - + - + - + - + -
P=0.003
B12 n=13 + - + -
P=0.01
Protective HLA
enriched during Follow-up:
59% at Year0 vs 75% at year5
Distinct influences:
HLA-B57 and B14 associated
to HIV control
HLA-B27 associated
to LTNPs
Antoni G, AIDS 2013
EACS B Autran 2013
• The Virus or the Host?
– Is it Immunity ?
• T cell adaptive Immunity:
HIV – Elite Controllers, LTNPs
• CD4 T cells ?
Function ?
Other parameters ?
• CD8 T cells ?
Specificity ?
Function ?
Gene associations ?
Correlates of protection ?
Is it the hen or the egg ??? EACS B Autran 2013
The ANRS Co-18 Cohort of HIV Controllers:
CD8 T cells mediate a strong anti-viral activity
p2
4 (
ng
/ml)
10 -1
10 0
10 1
10 2
10 3
10 4
HIC Control VIR ART
CD4:CD8 1:1
Mean
CD4 T cells
p24 log decrease (CD4 vs CD4:CD8 1:1) 0 1 2 3 4 5
IFNg
SF
C T
ota
l /1
06 P
BM
C
0
2000
4000
6000
8000
10000
12000
14000
16000 Spearman 0.836 p<0.0001
CD8 T cells from HIC
inhibit HIV production Saez-Cirion, PNAS 2008
Some correlation between anti-viral functions
of CD8 T cells from HIC
HIV inhibition and IFN-g production Saez-Cirion, JI 2009
EACS B Autran 2013
LTNP - ANRS-CO15 cohort: Robust HIV-specific CD8 T cells
17
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
EACS B Autran 2013
HIV Transcriptionally active
HIV Transcriptionally inactive
Anti gag CD8 T cells
HLA-B27/57pos
TN TCM TTM TEM
TN TTM TEM
HLA-B27/57 neg
TCM
Inflammation ++
Activation ++
Antigens Antigens Antigens
A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs
EACS B Autran 2013
• The Virus or the Host?
– Is it Immunity ?
• Antibodies ?
–Neutralizing ?
–Others ?
HIV – Elite Controllers, LTNPs
EACS B Autran 2013
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
• 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
DC-SIGN
VIH
gp41 gp12
0 CD4
CCR5,
CXCR4
Cell
Membrane
EACS B Autran 2013
LTNP , HIC and EC: Robust HIV-specific CD4 T cells
r = - 0,461;
p= 0,0001
Proviral DNA (log cp/106 cells)
1
10
100
1,000
10,000
1 2 3 4 5
An
ti-H
IV I
FN
g+
SF
C/m
illio
n
PB
MC
r = - 0,304 ;
p= 0,026
HIV-1 RNA (log copies / ml)
1
10
100
1,000
10,000
2 4 6 1
Time from inclusion (months)
100
80
60
40
20
60 48 36 24 12 0 0
Pro
po
rtio
n r
em
ain
ing
LT
NP
(C
D4
>6
00)
> 170 SFC and IgG2 (n=5)
> 170 SFC, No IgG2 (n=11)
< 170 SFC, and IgG2 (n=8)
< 170 SFC, No IgG2 (n=29)
P= 0.02
• 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 EACS B Autran 2013
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) EACS B Autran 2013
NO AIDS
Persistence of
HIV
Reservoirs
Current
AntiRetroVirals Can we
decrease the HIV
Reservoirs?
and
stop ART?
Functional
Cure ?
or
eradicate HIV
Sterilizing Cure ?
Are HIV / Elite Controllers, LTNPs
a model for HIV Cure?
EACS B Autran 2013
Hot Topic in 2013: Models of Cure ?
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)
Control HIV without ARV for median 3.5 years
After ARV for 5 years started at acute infection
No genetic background; Immunity ???
Preserved central-memory CD4 T cells
Low Immune activation
Sterilizing cure ?
• CCR5 defective stem cell graft ( Berlin patient )
Hoqueloux et al. AIDS 2010, J Antimicrob. Ther. 2013, Saez-Cirion et al. PLosPathogens, 2013
OR3
Year
98 99 00 01 02 03 04 05 06 07 08 09
GXR
RN
A c
op
ies/m
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OR1
Year
96 98 00 02 04 06 08 10
0
500
1000
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2000
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4+
T c
ells/m
m3
OR8
Year
98 99 00 01 02 03 04 05 06 07 08 09 10
OR2
Year
0
500
1000
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2000
CD
4+
T c
ells/m
m3
01 02 03 04 05 06 07 08 09 10 11 12 13
RN
A c
op
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l Year
CD
4+
T c
ells/m
m3
0
500
1000
1500
2000
96 98 00 02 04 06 08 10 12 R
NA
co
pie
s/m
l
Year
KPV
01 02 03 04 05 06 07 08 09 10 11 12 13
Year
04 05 06 07 08 09 10
JOGA
Year
02 03 04 05 06 07 08 09 10
MWP
Year
01 02 03 04 05 06 07 08 09
CXK
EACS B Autran 2013
Hot Topic in Sept 2013:
Potential strategies to reduce HIV reservoirs:
Lessons from LTNPs and HIC /ECs
Residual Replication
Immune Activation
HIV Reservoirs Latency
Reduce Systemic
Inflammation
Stimulate Anti-HIV immunity ???
NKT CD8
APC
What can we learn from
LTNPs, HIC & ECs for
Controling Latency ???
EACS B Autran 2013