Natural and induced control of HIV infection:differences and similarities

VISCONTI Study

Asier Sáez-Cirión, PhDUnité de Régulation des Infections Rétrovirales

Institut Pasteur, Paris, France

At least 5 years of infection, naïve of cARV, maintain 5 last viral loads < 400 copies

Buffassa et al, PLoS One 2011

HIV controllers (HIC): infected individuals

spontaneously controlling HIV-1 infection

Year01 02 03 04 05 06 07 08 09 10

CD4+

T c

ells

/mm

30

500

1000

1500

2000

HIV-

1 RN

A (c

opie

s/m

l pla

sma)

100101102103104105106107108109

Post-treatment controllers (PTC): infected individualscontrolling HIV-1 infection after interruption of cART

14 patientsMonths on cART : 36.5 (12-92)Months post-cART: 89 (48-115)

Therapy started within 10 weeks following Primary Infection (median 39 days p.i.)

Saez-Cirion et al PLoS Path 2013

1990 1995 2000 2005 2010

CD4

T ce

ll co

unts

/µl

0

200

400

600

800

1000

HIV-

1 RN

A (c

opie

s/m

l pla

sma)

0

500

1000

1500

2000

2500

HIV controllers and Post-treatment controllers different ways for a similar outcome

Post-treatment controllers had a tougher primary infection than HIV controllers

pre-HIC pre-PTC PRIMO Non controllers

CD4+

T c

ells

coun

ts a

t PHI

(c

ells/

µl)

200

400

600

800

1000

1200

pre-HIC pre-PTC PRIMO Non controllers

Plas

ma

RNA

Vira

l loa

d at

PHI

(log

copi

es/m

l)

0

2

4

6

8p=0.02

p=0.002p=0.88

p=0.68

Saez-Cirion et al PLoS Path 2013

Post-treatment controllers do not have a favorable MHC background

France HIC

Alle

le fr

eque

ncy

(%)

0

10

20

30

40

50

60

PTC

B27 B57 B35 B07

Saez-Cirion et al PLoS Path 2013

Saez-Cirion et al, JI 2009

R=0.836, p<0.00001

log p24 decrease (CD4 vs CD4:CD8 1:1)0 1 2 3 4 5

IFNg

SFC

tota

l/10

6 PBM

C0

2000

4000

6000

8000

10000

12000

14000

16000

Days post infection3 7 10

p24

(ng/

ml)

10-1

100

101

102

103

10 4

CD4 T cellsCD4:CD8 1:1

Saez-Cirion et al, PNAS 2007; Nature Protocols 2010

Efficient T cell responses are associated with natural control

• Greater and faster upregultaion of cytotoxic mediators Migueles, et al. Immunity 2008; Hersperger, et al. PLoS Pathogens 2010

% IL

-2+ C

D4+ T

cel

ls0.001

0.01

0.1

1

PHI HIC0.001

0.01

0.1

1

PHI HIC

% IF

Ng+ C

D4+ T

cells

0.001

0.01

0.1

1

10

PHI HIC0.001

0.01

0.1

1

10

PHI HIC

P=0.048

% IL

-2+ C

D8+ T

cel

ls

% IF

Ng+ C

D8+ T

cells

Lecuroux et al PLoS One, 2013

HICPHIlog

p24

decr

ease

(C

D4

vs C

D4:

CD

8 1:

1)0

1

2

3

4

5P < 0.001

Strong CD8- T cell capacity to suppress HIV-1 is usually absent in PHI

Median drop of -0.94 log HIV-1 RNA copies/ml within 7 days50 patients in PHI (median 35 days p.i.)

Post-treatment controllers have weak HIV-specific CD8+ T cell responses

VIR HAART HIClo

g p2

4 de

crea

se (C

D4 v

s CD4

:CD8

)0

1

2

3

4

<0.001

<0.001

VIR HAART HIC

IFNg

(SFC

/106 P

BMC)

0

2000

4000

6000

8000

10000

12000

IFNg ELISPOT

<0.001

<0.001

<0.01<0.01

PTC

<0.001

PTC

Saez-Cirion et al PLoS Path 2013

HIV suppression

Post-treatment controllers have weak levels of T cell activation

CD38+ HLA-DR+ CD38+HLA-DR+

% o

f CD3

+ CD

8+ ce

lls

0

10

20

30

40

50

60

70

HAARTHICPTC

p < 0.001

p < 0.001

Saez-Cirion et al PLoS Path 2013

Both HIC and PTC are infected with replication competent HIV-1

days of culture0 5 10 15 20 25 30p2

4 in

cul

ure

supe

rnat

ants

p24

(ng/

ml)

0.01

0.1

1

10

100

1000

Viral replication in CD4+ T cells from healthy donor

3538 patients included in the FHDH within 6 months of primary infection 1997-2011

756 patients treated within 6 months and at least for a year74 patients with a viral load below <50 RNA copies/ml who stop = 2% of PHI patients

Goujard et al Antivir Ther 2012: N=164 patients, 8.5% VL<50 at M24Hocqueloux et al AIDS 2010: N=32 patients, 15.6% VL<50 at M24

Probability to keep controlling infection at 24M (loss of control: 2VL>50 RNA copies/ml or 1VL>50 RNA copies/ml +cART) : 15.7% [6.5-28.5]

Months post-treatment interruption

Prob

abili

ty to

loss

cont

rol

Saez-Cirion et al PLoS Path 2013

A long-term treatment initiated during primary infection seems to increase the chances to control viremia

HIC vs PTC

HIV controllers (HIC)

Asymptomatic primary infection: low viral loads and high CD4 T cell counts in PHI

80% HIC carry one protective HLA-class I allele

Generally strong HIV-specific T cell responses with strong capacity to eliminate infected cells

Abnormal high levels of T cell activation

Estimated frequency: 0.5% of HIV infected patients

Post-Treatment Controllers (PTC)

Symptomatic primary infection: high viral loads and low CD4 T cell counts in PHI

57% PTC carry one HLA-class I allele associated with high viral loads

Generally very weak HIV-specific T cell responses with poor capacity to eliminate infected cells

Low levels of T cell activation

Estimated frequency: 5-15% of HIV infected patients interrupting a >12 months-length treatment initiated in primary infection

Exploring other mechanisms that have been proposed to contribute to natural control of infection…

Weak cell susceptibility to HIV-1 infection, contributing to limit the reservoirs in HIC

Innate immunity, NK cells, may contribute to limit replication in acute infection

Enhanced ADCC activity may contribute to control of infection, in particular in HLA-B*57neg HIC

Acknowledgements

Institut PasteurRégulation des Infections Rétrovirales

Gianfranco PancinoDaniel Scott-Algara

Françoise Barré-SinoussiAnnie David

Pierre Versmisse Faculté de Médecine Paris SudINSERM U1012

Alain VenetOlivier Lambotte

Jean-François DelfraissyCécile GoujardIsabelle Girault

Camille Lecuroux

INSERM U1018Laurence Meyer

Faroudy Boufassa

CHU Necker Enfants MaladesLaboratoire de Virologie

Christine RouziouxVéronique Avettand-Fenoel

Adeline Mélard

CHR Orléans La SourceService Maladies Infectieuses

Laurent HocquelouxThierry Prazuck

CHU Hôtel-DieuUnité Immuno-Infectiologie

Jean-Paul Viard

ANRS CO18 “HIV controllers”

ANRS CO15 “ALT”

Patients and clinicians who participate in the studyCHU Pitié-SalpetriereINSERM UMR-S 945

Brigitte AutranCharline Bacchus

Benjamin DescoursAssia Samri

Ioannis TheodorouJulien Guergnon

ANRS CO6 “PRIMO”

INSERM UPMC U943Dominique Costagliola

Valérie Portard

FHDH“French Hospital Database on HIV”