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The C-type lectin surface receptor DCIR contributes to trans- and cis - infection pathways. 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 - PowerPoint PPT Presentation
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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