1. 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

2. HIV and Immune Deficiencies :
Are CD4 defects & AIDS the only complication of the HIV infection?
The collateral damages of Immune activation…
Immune Responses
Immune Activation
CD4/mm3
Pl VL
200
AIDS
Opportunistic
Infections
ARV
0 3-6 m years
B Autran EACS 09

3. Chronic Inflammation/activation plays a key role in immunopathology of HIV
tat,
Appay V et al, J Pathol 08

4. 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

5. 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
(AIDS symptoms or CD4 non necessary)
EACS B Autran 2013

6. 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 > = 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%
Elite LTNP:
= 40% HIC
= 32% EC
= 60% detectable plVL
Elite Controlers:
= 46% LTNP
= 12% Elite LTNP
= 25% CD4 < 500/mm3
EACS: B Autran 2013

7. 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:
Nb CD4>600
Number subjects
Years
9 (44%) 18
8 (33%) 24 5
12 (40%) 30 4
17 (27%) 44 3
28 (46%) 61 2
46 (65%) 71 1
EACS B Autran 2013

8. 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

9. ALT-ANRS CO15 cohort: HIV characteristics at entry:
It is NOT the Virus !
Low but Heterogeneous viral production:
Median plasma VL =
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 1 10
100
1000
10000
100000
HIV DNA
HIV RNA
Elite
Controlers
Viremic
Slow Progressors
Low Reservoir (cell associated HIV-DNA)
correlated to virus production
B.A.EACS 2013

10. Low HIV Reservoir (HIV-DNA) in PBMC : associated with a low risk of HIV disease progression
HIV DNA Log copies/106 PBMC
The DNA results are interesting when the different aspects of HIV infection is considered : this slide is from Pr C Rouzioux at Necker hospital
You can see the DNA results fromdifferent groups of HIV infected patients
A low amount of HIV DNA is associated with a low risk of HIV disease progression as you see the largest amounts of HIV DNA in patients during primary infection, then chronically infected untreated, then treated pts, then the results of the french LTNP cohorts, ALT is for asymptomatc long term who are defined according to immunological criterai and HIC with the lowest amount of HIV DNA
PRIMO Progressors PRIMO LTNP HIV-controllers
infection SEROCO treated ANRS Co ANRS Co-18 10
S Lewin & C Rouzioux et al. AIDS 2011 10

11. 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

12. 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 ?
EACS B Autran 2013

13. is the strongest Marker
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
(Dalmasso et al.)
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)
Lower Reservoir
(HIV-DNA)
in B27+/57+
vs negatives
B Descours et al.
Clin. Inf. Dis 2011 13
EACS B Autran 2013

14. It is the HOST ! ANRS-CO15 (ALT) cohort: Immune Genetics of LTNPs :
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)
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 1 2 3 4 5
TOTAL
HLA
B57 n=19
B27 n =14
B14 n=14
Median log10 HIV
HIV-RNA Cp/mL
HIV-DNA Cp/Million PBMC
P=0.003
B12 n=13
P=0.01
EACS B Autran 2013

15. HIV – Elite Controllers, LTNPs
The Virus or the Host?
Is it Immunity ?
T cell adaptive Immunity:
CD4 T cells ?
Function ?
Other parameters ?
CD8 T cells ?
Specificity ?
Gene associations ?
Correlates of protection ?
Is it the hen or the egg ???
EACS B Autran 2013

16. The ANRS Co-18 Cohort of HIV Controllers: CD8 T cells mediate a strong anti-viral activity
p24 (ng/ml) 10 -1 1 2 3 4
HIC
Control
VIR
ART
CD4:CD8 1:1
Mean
CD4 T cells
CD8 T cells from HIC
inhibit HIV production
Saez-Cirion, PNAS 2008
p24 log decrease (CD4 vs CD4:CD8 1:1) 1 2 3 4 5
IFNg SFC Total /106 PBMC
2000
4000
6000
8000
10000
12000
14000
16000
Spearman 0.836
p<0.0001
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

17. 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 17
EACS B Autran 2013

18. A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs
HLA-B27/57pos TN
TCM
TTM
TEM
HLA-B27/57 neg
Inflammation ++
Activation ++
Antigens
HIV Transcriptionally active
HIV Transcriptionally inactive
Anti gag CD8 T cells
EACS B Autran 2013

19. HIV – Elite Controllers, LTNPs
The Virus or the Host?
Is it Immunity ?
Antibodies ?
Neutralizing ?
Others ?
EACS B Autran 2013

20. 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
gp120
CD4
CCR5, CXCR4
Cell
Membrane
EACS B Autran 2013

21. 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 2 3 4 5
Anti-HIV IFNg+ SFC/million PBMC
r = - 0,304 ; p= 0,026
HIV-1 RNA (log copies / ml) 6
Time from inclusion (months) 80 60 40 20 48 36 24 12
Proportion remaining LTNP (CD4>600)
> 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
I will be brief about the CD4 T cell responses in HIC as I have shown you some of these results last time
HIC have HIV specific CD4T cells as shown by the production of infg but also IL2 and mip1alpha in response to p24gag stim
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

22. 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

23. 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 ?
EACS B Autran 2013

24. 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 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 ???
Low Immune activation
OR3
Year 98 99 00 01 02 03 04 05 06 07 08 09
GXR
RNA copies/ml
OR1 96 10
500
1000
1500
2000
CD4+ T cells/mm3
OR8
OR2 11 12 13
KPV
JOGA
MWP
CXK
Hoqueloux et al. AIDS 2010, J Antimicrob. Ther. 2013, Saez-Cirion et al. PLosPathogens, 2013
EACS B Autran 2013

25. Potential strategies to reduce HIV reservoirs:
Hot Topic in Sept 2013:
Potential strategies to reduce HIV reservoirs:
Lessons from LTNPs and HIC /ECs
Stimulate
Anti-HIV immunity ???
NKT
CD8
APC
Immune Activation
Residual Replication
Reduce Systemic Inflammation
HIV Reservoirs
Latency
What can we learn from
LTNPs, HIC & ECs for
Controling Latency ???
EACS B Autran 2013