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The C-type lectin surface receptor DCIR contributes to trans- and cis - infection pathways

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

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The C-type lectin surface receptor DCIR contributes to trans- and cis - infection pathways

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  1. The C-type lectin surface receptor DCIR contributes to trans- and cis- infection pathways Alexandra Lambert, MSc

  2. 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 Lumen of vagina Cervicovaginal epithelium Submucosal epithelium Pope M. IAVI 2004 Brenchley et al J. Exp Med 2004

  3. Dendritic cell transmit HIV-1 to T cells by two mechanisms • Transfer of HIV-1 after de novo virus production : cis-infection Virion CCR5 CD4 Viral DNA Dendritic cells De novo HIV-1 production Late transfer or cis-infection CD4+ T cells

  4. 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 Virion CCR5 CD4 Early transfer or trans-infection Dendritic cells CD4+ T cells

  5. C-type lectin receptor family Figdor C. G. et al, 2002 Nat. Rev. Immunol

  6. 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

  7. HIV-1 exploits DCIR to bind to DC and to be transferred to CD4 T cell Decrease of 30% of transfer 7 6 5 4 p24 (ng/ml 3 *** 2 1 0 Untreated (control) Non-specific siRNA DCIR-specific siRNA Lambert A.A et al., 2008 Blood

  8. DCIR is involved in trans-infection Donor 1 Donor 2 Negative control cell culture Non-specific siRNA 20 DCIR-specific siRNA * 15 ** p24 (ng/ml) 10 ** 5 0 without efavirenz with efavirenz 2.5 EFA X * Trans-infection or Early transfer 2.0 * 1.5 ** p24 (ng/ml) 1.0 0.5 0.0 without efavirenz with efavirenz Lambert A.A et al., 2008 Blood

  9. DCIR is involved in cis-infection 60 Untreated (control) Non-specific siRNA 50 * 50 DCIR-specific siRNA Untreated (control) Non-specific siRNA 40 40 DCIR-specific siRNA p24 (ng/ml) 30 30 p24 (ng/ml) 20 * * 20 10 10 0 2 4 6 0 Days of coculture 2 4 6 Days of co-culture Cis-infection or Late transfer Significative descrease of the amount of transferred virus Lambert A.A et al., 2008 Blood

  10. DCIR is involved in productive infection In DC In Raji CD4 Untreated (control) Non-specific siRNA 30 800 DCIR-specific siRNA * Raji-CD4/DCIR- Raji-CD4/DCIR+ 20 600 p24 (ng/ml) p24 (ng/ml) 400 10 100 0 0 3 6 9 Days post-infection 0 3 6 9 Days Post-infection Infection with de novo production Lambert A.A et al., 2008 Blood

  11. Importance of the DCIR neck domain for HIV-1 binding Raji-CD4/DCIR- * Raji-CD4/DCIR+ 25 20 15 p24(ng/ml) 10 Raji-CD4/DCIR- 5 Raji-CD4/DCIRΔneck 25 0 20 Raji-CD4/DCIR- Raji-CD4/DCIR+ 15 p24 (ng/ml) 10 5 0 Raji-CD4/DCIR- Raji-CD4/DCIRΔneck Lambert A.A et al., 2008 Blood

  12. Importance of the neck domain for virus infection DCIR wild type DCIR Δ neck 800 * Raji-CD4/DCIR- Raji-CD4/DCIR+ 600 1500 * Raji-CD4/DCIR- Raji-CD4/DCIRΔneck p24 (ng/ml) 400 1000 p24 (ng/ml) 100 500 0 3 6 9 0 Days Post-infection 3 6 9 Days Post-infection Lambert A.A et al., 2008 Blood

  13. 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

  14. Acknowledgments Michel 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

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