« Toward an HIV Cure: Learning from Viral Control off-ART »

Françoise BARRÉ-SINOUSSIInstitut Pasteur, Paris

CFAR & IAS SeminarJohns Hopkins University

Sommer Hall, Bloomberg School of Public Health

Baltimore, December 8, 2015

Key scientific challenges and Priorities in HIV science

HIV Vaccine discovery Comorbidities on ART HIV Cure discovery Still no correlates of

protection but significant progresses

in HIV vaccine research with new

perspectives since the Thai trial in 2009..

HIV infection, a chronic condition on life long cART

but non AIDS related

comorbidities

Persistent HIV infection on HAART is the main hurdle

science must tackle to achieve an HIV

“Cure”

Better knowledge on HIV basic science on latency, immunology

and pathogenesis

Novel Vaccine and Therapeutic Strategies?

“Which kind of “HIV Cure” are we looking for?

Elimination of all latently infected cells

Persistent reduction and control:Long term health without cART

and without risk to transmit

HIV Reservoirs on cART….

Berlin Patient? Proof of concept…

CurecART free

sustainable Remission

Better definition/

communication?

Cases of “Remission” post-very early treatmentANRS EP 47 VISCONTI: 20 HIV+ patients (5-15%) treated at about 10w PI for 3 years, ≈10 years off treatment (no favorable HLA, no efficient CD8T cell response, small reservoirs; very weak T cell activation)

VISCONTI Like teenager: ART at birth; at least 12 years in remission..…

Cases of Natural ControlSIV infected African NHP: active replication in blood but low reservoirs in LN and attenuated inflammation/immune activation related to no gut destruction, no microbial translocation and peculiar very early innate response (IFN-I, ISG, strong NK activation…)

HIV Controllers: <0.3% of HIV+ people, no cART, natural control of HIV infection (cell restriction to HIV, lower T cell activation, HLA B57/B27, efficient CD8T cell response related to NK cell activation)

Why do we are optimistic about at least cART free disease remission?

What can we learn from post-treatment controllers (PTC) ?

« Patients in remission? ». Why?

ANRS VISCONTI study: 14 PTCsStart cART: median 39 days p.i.Months on cART : median 3 years Months post-cART: > 10 years

cARTSTART STOP

vire

mia

years>1 year

756

cART

1013

PHI

3538

Stop cARt

Num

ber o

f ind

ivid

uals

0

1000

2000

3000

4000

% o

f PTC

70

French HIV data base (FHDH ANRS CO4): www.ccde.fr128117 patients (mean of follow up: 7 years)

- 1 loss of control at 6 years- 1 PTC with repeated low level replication

PTC are infected with replication competent HIV-1

Saez-Cirion et al PLoS Path 2013

PRIMOHIC

PRIMOPTC

PRIMO Non controllersPl

asm

a RN

A Vi

ral l

oad

at P

HI(lo

g co

pies

/ml)

0

2

4

6

8 p=0.002 p=0.68

PTC displayed high viremia during primary infection

The virus can replicate in CD4+ T cells from each

patient

The ANRS International VISCONTI Post-Treatment Controller Cohort

20 PTC

Coordinators: A Saez-Cirion (HIPer, IP) & C Rouzioux (Necker)

7 new PTC, all early treated post-infection (Time off therapy: 6.5 years [2.8-14.0])

6 PTC from the ANRS iVISCONTI: 3 in the USA, 2 in Spain, 1 in Germany1 teenager PTC: a paediatric case of durable remission

Durable cART free remission in a perinatally infected teenager (French Pediatric Cohort ANRS EPF-CO10)

HIV-1 viral load and CD4+ T cell counts in the child.

Age (days)0 500 1000 1500 2000

% C

D4 cells0

10

20

30

40

50

Viral load (HIV R

NA copies/m

l plasma)

101

102

103

104

105

106

107ZDV

ZDV

+DD

I+3TC+R

TVD

DI+3TC

+RTV

DD

I+D4T+R

TV

DD

I+D4T+R

TV

Age (years)6 8 10 12 14 16 18

% C

D4 cells in blood

0

10

20

30

40

50

510

48

HIV-1 RNA: <9 copies/ml of plasma 2013 <4 copies/ml of plasma 2014<7 copies/ml of plasma 2015

HIV-1 DNA: 2.1-2.5 log copies/10^6 PBMC between 2013-2015Low levels of replicating viruses detected in vitro

P. Frange et al. The Lancet HIV, 2015

75,1

9097

,000

ART 6 years

STO

P

PHI

Chro

nic

cART AL

THI

CPT

C

HIV-

DNA

(log1

0 co

pies

/106 P

BMC)

1

2

3

4

5

6

Saez-Cirion, Plos Path, 2013

Hocqueloux et al, JACS 2013

years under cART

HIV

DNA

(Log

/ M

PBM

C)started inprimary infection

started in chronic infection

Treatment during primary HIV infection has a major impact on the size of the viral reservoir

Hocqueloux et al, JAC 2013

A low viral reservoir is necessary but not sufficient for HIV remission.. What else ?

cART :

HIV reservoirs in PTC:- - Mostly TTM subset- - weak in TN and TCM subsets

France HIC

Alle

le fr

eque

ncy

(%)

0

10

20

30

40

50

60B27 B57 B35 B07

Non favorable HLA and Weak CD8 T cell responses in PTC

Frange et al The Lancet HIV. 2015

PTC

Very weak HIV-specific CD8+ T cell responses detected in PTC

Saez-Cirion et al PLoS Path 2013

CD8+ T cells

PTC cART HIC

% of C

D127+ on C

D8+ T cells

30

40

50

60

70

80

90

CD8+ T cells

PTC cART HIC

% of C

CR

7+ on CD

8+ T cells

0

10

20

30

40

50

60

CD4+ T cells

PTC cART HIC

% of C

D127+ on C

D4+ T cells

65

70

75

80

85

90

95

CD4+ T cells

PTC cART HIC%

of CC

R7+ on C

D4+ T cells

10

20

30

40

50

60

70

Samri et al IAS 2015

CD8 T cell response

CD8+ T cells

PTC cART HIC

% of C

D127+ on C

D8+ T cells

30

40

50

60

70

80

90

CD8+ T cells

PTC cART HIC

% of C

CR

7+ on CD

8+ T cells0

10

20

30

40

50

60

CD4+ T cells

PTC cART HIC

% of C

D127+ on C

D4+ T cells

65

70

75

80

85

90

95

CD4+ T cells

PTC cART HIC

% of C

CR

7+ on CD

4+ T cells

10

20

30

40

50

60

70

CD4 T cell response

CD8+ T cells

PTC cART HIC

% of C

D38+ on C

D8+ T cells

5

10

15

20

25

30

CD8+ T cells

PTC cART HIC

% of H

LADR

+ on CD

8+ T cells

0

10

20

30

40

50

60

CD8+ T cells

PTC cART HIC

% of D

R+C

D38+ on C

D8+ T cells

0

2

4

6

8

10

12

14

16

18

PTC maintain control with low level of immune activation

HD VIR HIC PTC cART

CD69 NK cells

Scott-Algara et al CROI 2015

Saez-Cirion et al PLoS Path 2013

HD cART PHI PTC cART CHI HIC

IP-10 (pg/ml)

101

102

103

104p<0.05

p<0.05

Plasma IP-10

Monceaux et al Unpublished

PTC NK cells have with high anti-HIV activity

Scott-Algara et al CROI 2015

NK cells from PTC have better capacity to control HIV infection in autologous CD4 T cells (measured by lower expression of p24 and GFP)

HD VIR HIC PTC cART HD VIR HIC PTC cART

HD VIR PTCcARTHD PTCVIR cART

% o

f rel

ative

infe

ction

(C

D4 v

s NK:

CD4

1:1)

% o

f rel

ative

infe

ction

(C

D4 v

s NK:

CD4

1:1)

A peculiar subset of NK cells involved in

controlling HIV in PTC?

PTC NK cells are phenotypically and functionally different from EC NK

Open questions : Are NK cells preserved to control HIV infection

in early treatment?? (Alter et al. 2015)Is this NK phenotype and function related to

PTC genetic determinants ??

NK cell

IFN-γCytokines ?

KIR2DL1

KIR2DL2KIR3DL1

NKG2A

CD160 negNKp46 low

Low cytotoxicCapacity?

Target cell

HLA ???

NK cells from PTC have a peculiar phenotype:

- Higher expression of CD158a, CD158b and NKG2A than EC and HD- Lower expression of NKp46, CD160 and CD69-High capacity to produce IFN-γ, but normal degranulation (CD107a)

High capacity to control HIV?

Similarities with non pathogenic

SIVagm infection in AGM?

AGM MAC

0

20

40

60

80

100

150 days P.I

% o

f IL-

15 fo

llicl

es/L

N se

ctio

n

AGMMAC

F

MAC

IL-15 in lymph node follicles

AGM

Higher NK cell activity in LN during SIVagm (non-pathogenic) compared to SIVmac infection (pathogenic)

% of IL-15+ follicles

AGMCD107+ NK

MACCD107+ NK

PerforinIFN-gCD107

AGM/SIV+ chronic phase

NK cells in AGM LN follicles

Green: B cellsYellow: NK cells

No SIV replication in LN follicles

Macaque model of post-treatment controlEarly vs delayed start of treatment

vire

mia SIVmac / macaque

Impact on viral reservoirs, inflammation and immune responses ?Mechanisms responsible for remission ? Biomarkers predictive of control after treatment interruption ?

HIV Cure strategies: Lessons from Long-term control in human and NHP

To limit the establishment of the

reservoir

To reduce the size of the reservoir

Flush out the latent

reservoir

Deplete infected cells

Render uninfected

cells resistant to HIV

Early ART

Strategies to optimize innate and adaptive immune functions to: - facilitate clearance of infected cells- enhance immune control 

2014-2016 Global Scientific Strategy Six themes and subgroups:

Molecular Biology of HIV latency and shock strategies (Moncef Benkirane & David Margolis)

Viral reservoirs, immunology of HIV persistence and kill strategies (Steven Deeks & Daniel Douek)

Models for HIV cure or sustainable remission (Jintanat Ananworanich & Jeffrey Lifson)

Gene/Cell Therapy (Paula Canon & Daniel Kuritzkes) Novel Biomarkers and technologies to quantify/analyse HIV

reservoirs (Sharon Lewin & John Mellors) Social sciences and health system preparedness (Joseph Tucker & Ying-

Ru Lo)

July 2016: Publication and Launch of the revised Global Scientific Strategy at the AIDS 2016 in Durban.

Thanks you to…

And to all the patients, researchers and health professionals who participate to HIV cure research…

JF. Delfraissy, O. Lambotte,C. Rouzioux, L. Hocqueloux, P. Frange...

M. Muller-Trutwin, A.Saez-Cirion

D. Scott-AlgaraAnd many others…

S. Deeks, S. Lewin and all the members of the IAS HIV Cure ISWG members

J. Whitescarver and all the members of the IAS HIV Cure Advisory Board

AL. Ross and R. Lamplough