The Journal of Experimental Medicine
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Published 15 November 2004. doi:10.1084/jem.20041356
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 10, 1279-1288
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DC-SIGN–mediated Infectious Synapse Formation Enhances X4 HIV-1 Transmission from Dendritic Cells to T Cells

Jean-François Arrighi1, Marjorie Pion1, Eduardo Garcia1, Jean-Michel Escola1, Yvette van Kooyk2, Teunis B. Geijtenbeek2, and Vincent Piguet1

1 Department of Dermatology and Venereology, University Hospital of Geneva, 1211 Geneva, Switzerland
2 Department of Molecular Cell Biology and Immunology, VUMC, 1081 BT Amsterdam, Netherlands

Address correspondence to Vincent Piguet, Dept. of Dermatology and Venereology, University Hospital of Geneva, 4-752, 24 Rue Micheli-du-Crest, 1211 Geneva, Switzerland. Phone: 4-1-22-372-94-65; Fax: 4-1-22-372-94-70; email: vincent.piguet{at}medecine.unige.ch

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC–T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient.

Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA–expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN– DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC–T cells conjugates.

Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.

Key Words: HIV/SIV • virological synapse • RNA interference • lentiviral vectors • trans infection

J.-F. Arrighi and M. Pion contributed equally to this work.

Abbreviations used in this paper: MOI, multiplicity of infection; si, small interfering.


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