Alexandra Lambert, MSc

Dendritic cells (DC) play an important role in primo-infection

Capture HIV-1 by their dendrites

DC are susceptible to infection but less than CD4

Permit transport of HIV-1 to lymph nodes hidden from immune system

Submucosal epithelium

Lumen of vagina

Cervicovaginal epithelium

Pope M. IAVI 2004

Brenchley et al J. Exp Med 2004

CD4

CCR5

CD4+ T cells

Dendritic cells

Virion

Dendritic cell transmit HIV-1 to T cells by two mechanisms

Transfer of HIV-1 after de novo virus production : cis-infection

Viral DNA

De novo HIV-1 production

Late transfer or cis-infection

CD4+ T cells

Dendritic cells

Virion

Dendritic cells transmit HIV-1 to T cells by two mechanisms

Transfer of HIV-1 without de novo virus production : trans-infection

Attachment receptors :-C-type lectin receptors (DC-SIGN, mannose receptor, etc…)-Syndecan 3-Other

CD4

CCR5

Early transfer or trans-infection

C-type lectin receptor family

Figdor C. G. et al, 2002 Nat. Rev. Immunol

What is DCIR? DCIR : Dendritic Cell Immuno Receptor

It is a member of C-type lectin receptor family but little is known about the function of this receptor because there are few studies about it (Bates et al J. Immunol

1999)

It is found on the surface of B cells, monocytes, macrophages, neutrophiles (Bates et al J. Immunol 1999) and also found on CD4 T cell in arthritis patients (Eklöw et al Ann Rheum

Dis 2008)

No ligand identified yet

HIV-1 exploits DCIR to bind to DC and to be transferred to CD4 T cell

Untreat

ed (c

ontrol)

Non-spec

ific

siRNA

DCIR-s

pecifi

c si

RNA

0

1

2

3

4

5

6

7

***p2

4 (

ng

/ml

Lambert A.A et al., 2008 Blood

Decrease of 30% of transfer

DCIR is involved in trans-infection

0

without efavirenz with efavirenz

5

10

15

20

**

*

**

p24

(n

g/m

l)

Non-specific siRNADCIR-specific siRNA

Negative control cell culture

without efavirenz with efavirenz0.0

0.5

1.0

1.5

2.0

2.5

**

*

*

p24

(n

g/m

l)

Trans-infection or Early transfer

EFA

X

Lambert A.A et al., 2008 Blood

Donor 1 Donor 2

DCIR is involved in cis-infection

2 4 60

10

20

30

40

50

60 Untreated (control)

Non-specific siRNA

DCIR-specific siRNA

*

Days of coculture

p2

4 (

ng

/ml)

2 4 60

10

20

30

40

50

Days of co-culture

*

p2

4 (

ng

/ml)

*

Untreated (control)

Non-specific siRNA

DCIR-specific siRNA

Cis-infection or Late transfer

Lambert A.A et al., 2008 Blood

Significative descrease of the amount of transferred virus

DCIR is involved in productive infection

0 3 6 90

10

20

30

Untreated (control)

Non-specific siRNA

DCIR-specific siRNA

Days post-infection

p2

4

(ng

/ml)

Lambert A.A et al., 2008 Blood

Infection with de novo production

3 6 90

100

Raji-CD4/DCIR-

400

600

800

Raji-CD4/DCIR+

*

Days Post-infection

p2

4 (

ng

/ml)

In DC In Raji CD4

Importance of the DCIR neck domain for HIV-1 binding

Raji-CD4/DCIR- Raji-CD4/DCIR+0

5

10

15

20

25

Raji-CD4/DCIR-Raji-CD4/DCIR+ *

p2

4 (

ng

/ml)

Raji-CD4/DCIR- Raji-CD4/DCIRΔneck0

5

10

15

20

25

Raji-CD4/DCIR-Raji-CD4/DCIRΔneck

p2

4 (

ng

/ml)

Lambert A.A et al., 2008 Blood

Importance of the neck domain for virus infection

3 6 90

500

1000

1500

Raji-CD4/DCIR-

Raji-CD4/DCIRΔneck

*

Days Post-infection

p2

4 (

ng

/ml)

Lambert A.A et al., 2008 Blood

3 6 90

100

Raji-CD4/DCIR-

400

600

800

Raji-CD4/DCIR+

*

Days Post-infection

p2

4 (

ng

/ml)

DCIR wild type DCIR Δ neck

Summary of findings

HIV-1 can use DCIR as an attachment factor on the surface of DC

DCIR participates to productive infection of DC and DC-mediated virus transfer to CD4 T cells

Neck domain of DCIR is important for virus binding and infection

Lambert A. A, Gilbert C, Tremblay M.J.The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1-1 in

dendritic cells and contributes to trans- and cis-infection pathways.2008, Blood, Epub ahead of print

AcknowledgmentsMichel J. Tremblay (my supervisor)Caroline Gilbert (my co-supervior)

All members of the Michel J. Tremblay’s Lab

CIHR Doctoral Award and Operating grant (MOP-79542)

- HIV-1/AIDS Research Program

Project leaders:Project leaders:Réjean Cantin PhDCorinne Barat PhDMichel Ouellet PhDRobert Lodge PhD

Postdocs:Postdocs:Ravendra GargPranav Kumar

PhD studentsPhD students:: Simon MercierMichaël ImbeaultSandra ThibaultSonia GauthierJuliette DiouJonathan Bertin Lise-Andrée Gobeil

Research assistants Research assistants Nathalie Trudel

MSc studentsMSc students:Diane MalaisonAudrey PlanteAlexis DanyloKatia Giguère

Technical assistants:Technical assistants:Marc-André RoyCaroline CôtéRenaud Tremblay