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

brigitte.autran@psl.aphp.fr

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

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CD4_S0 CD4_S1 CD4_S2 CD4_S3 CD4_S4

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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

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HIV DNA

HIV

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Elite

Controlers

Viremic

Controlers

Viremic

Slow Progressors

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ARNJ0 ARNS1 ARNS2 ARNS3 ARNS4

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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

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l /1

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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)

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60

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60 48 36 24 12 0 0

Pro

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em

ain

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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

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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