Abstract
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.
Original language | English |
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Pages (from-to) | 1279-88 |
Number of pages | 10 |
Journal | Journal of Experimental Medicine |
Volume | 200 |
Issue number | 10 |
DOIs | |
Publication status | Published - 15 Nov 2004 |
Keywords
- Antibodies, Monoclonal
- Binding Sites
- Cell Adhesion Molecules/metabolism
- Cells, Cultured
- Dendritic Cells/metabolism
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Genetic Vectors
- HIV Infections/metabolism
- HIV-1/metabolism
- Humans
- Lectins, C-Type/metabolism
- Lentivirus/genetics
- Microscopy, Fluorescence
- RNA, Small Interfering/genetics
- Receptors, Cell Surface/metabolism
- T-Lymphocytes/metabolism