Laboratoire Immunité & Infection INSERM UMR-S 945 IFR 113 Paris, France

Laboratoire Immunité & InfectionINSERM UMR-S 945IFR 113Paris, France

P DEBRE

Specific phenotypic and functional features of natural killer cells from HIV-infected

long-term non progressors and HIV controllers

HIV, CD4 & NK cells

PATHOGENESIS

NK ?

CD4 non infected cellsVirus

CD4 infected cells

INFECTION

LTNP and HIV-Controllers

• HIV seropositive

• Antiretroviral untreated

•CD4 count (nadir):•LTNP : >600/mm3

•HIV-controllers: Variable

• Viral load :•LTNP : Uncontrolled•HIV-controllers: Undetectable

The proportion of individuals who become LTNP and HIV- controllers is not known, but is estimated to be ~ 0.5 and 0.1%, respectively.

Characteristics of Healthy donors and HIV-infected patients : ALT cohort

Increased proportion of CD56bright and CD56-CD16+ NK-cell subsets in LTNP and HIV-controllers

% C

D3- C

D5

6+

UI PROG LTNP CONT0

5

10

15

20

25*

% C

D56

bri

gh

t

25

UI PROG LTNP CONT

******

% C

D56

- /CD

16+

0

10

20

30

40

50

UI PROG LTNP CONT

******

***

5

10

15

20

25

CD56bright

NKG2A

2B4

NKp30

NKp46

NKp80

DNAM-1

CD16

CRAAC

CD161

LAIR-1

CD94

CD158a

CD69

NKG2D

CD158e

NKG2C

CD158b

NKp44

ILT2

HLA-DR

PR

OG

10

PR

OG

2P

RO

G6

PR

OG

1P

RO

G3

PR

OG

8P

RO

G7

PR

OG

14

PR

OG

12

PR

OG

13

PR

OG

11

UI5

LTN

P1

UI7

UI9

UI4

UI1

UI1

1U

I3U

I2U

I10

UI6

UI8

UI1

2LT

NP

4LT

NP

6

LTN

P8

LTN

P9

LTN

P1

2P

RO

G4

PR

OG

9P

RO

G1

5

LTN

P7

LTN

P1

6

LTN

P1

5

LTN

P1

4P

RO

G5

LTN

P3

LTN

P5

LTN

P1

8LT

NP

2LT

NP

17

LTN

P11

LTN

P1

9LT

NP

13

CO

NT

1

LTN

P1

0

CO

NT

2

CO

NT

3C

ON

T4

CO

NT

6C

ON

T8

CO

NT

5C

ON

T7

CO

NT

9

PROG UI LTNP CONT

Specific phenotypic patern of NK-cell markers from LTNP and HIV-controllers

CD56+ CD56-/CD16+%

IF

N-g

0

25

50

75

0

25

50

75*

**

UI PROG LTNP CONT UI PROG LTNP CONT

% C

D10

7a

0

25

50

75

100

0

25

50

75

100

UI PROG LTNP CONT UI PROG LTNP CONT

***

Increased proportion of IFN-g production in LTNP and HIV-controllers

NKp44L expression by CD4+ T cells from HIV-infected patients

Kill

NK

CD4

+-NKp44

MHC-I NKp44L

Vieillard et al Proc Natl Acad Sci USA (2005)

% NKp44L

0

10

20

30

40

3- 3-4+ 4+8+ 8+

Control PBMC HIV+ PBMC CD4 / mm3

0 250 500 750 10000

10

20

30

40

p=0.002

% NKp44L

E/T ratio

0

10

20

30

40

100/150/1 25/112.5/1

44L+

44L-

% NK Lysis

0.1 1 10 100 1000

viral load(x 1000)

0

10

20

30

40

% NKp44L

p=0.005

Epitope 3S(SWSNKS)

CD4+ T cell

HIV infected cells

HIV virion

gp41

NKp44L

CD4+ T cell lysis

CD4+ T cell depletion ?

Autologous NK cells

Anti-3S Ab

NKp44

In vitro ex vivo

HIV1-infected individuals

CD4+NKp44L+ cell

E/T ratio

0

10

20

30

40

100/150/125/112.5/1

44L+

44L-

% NK Lysis

CD4 count

% N

Kp

44L

PROG

0 250 500 750 1000 12500

10

20

30

LTNP

0 250 500 750 1000 1250

CONT

0 250 500 750 1000 1250

R2=0.862

p=0.0031

R2=0.592

p=0.0001

R2=0.019

p=0.5235

Low expression of NKp44L by CD4+ T cells from LTNP

and HIV-controllers

Low level of cytotoxicity of NK cells from LTNP and HIV-controllers against autologous CD4+ T cells : Relationship with NKp44L expression

% N

K ly

sis

#10 (24%)

#2 (<1%)

E/T ratio

#9 (3%)

40/1 20/1 10/1 5/1 40/1 20/1 10/1 5/1 40/1 20/1 10/1 5/1

#1 (<1%)

#18 (6%)

#9 (13%)

#1 (22%)

#10 (<1%)

#1 (18%)

CONTLTNPPROG

#8 (3%)

0

20

40

60

#10 (<1%)

40/1 20/1 10/1 5/1

0

20

40

60

0

20

40

60 #1 (<1%)

UI

Conclusions

1 - Different proportion of NK-cell subsets in LTNP and HIV- controllers

✔ Specific pattern of NK-cell markers in LTNP and HIV-controllers

✔ Higher production of IFN-g in HIV-controllers

✔ Low expression of NKp44L on CD4+ T cells from LTNP and HIV- controllers

✔ Low sensitivity of NK cells from LTNP and HIV-controllers against autologous CD4+ T Cells

Conclusions

2 – Switch of repertoire and function of NK cells during HIV infection

✔ Controllers: increase IFN production and no autologous cytotoxicity

control of viral replication

✔ Progressor: autologous cytotoxicity and no IFN increase

depletion of CD4 cells

✔ LTNP: intermediate

Unité Immunité & Infection

Team-2

Patrice Debré

Hugues Fausther Bovendo

Vincent Vieillard

Team-1

Brigitte Autran

Assia Samri

Unité Epidémiologie

Clinique

Dominique Costagliola

GrantsEuropean program « Gysheal »

ANRS

Bill & Melinda Gates Foundation

Service de Virologie

Henri AgutDaniel Candotti

Service des Maladies

Infectieuses & Tropicales

Christine Katlama

Pité-Salpêtrière Hospital, Paris

Partners