11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11;11:abstract no. 44

David McDonald, T J Hope
Univ of Illinois, Chicago, USA

BACKGROUND: Monocyte-derived dendritic cells (DC) efficiently bind and internalize HIV but are not easily infected by the virus despite adequate expression of entry receptors. Instead, DC can transmit infectious HIV to target cells, effectively completing an intracellular phase of the virus life cycle in the absence of replication. We have previously shown that the transmission of HIV from DC to target cell is accomplished by recruitment of the virus and its receptors to sites of DC-target cell contact and proposed that DC enhance infectivity through the formation of an "infectious synapse" that brings virus and receptors into proximity on the target cell surface.

RESULTS: We found that LPS-activated DC were much better than immature DC at both recruiting HIV and transmitting infection. Virus in the activated DC was often concentrated into a single subcellular region, both proximal and distal to the site of T-cell contact. Immunofluorescent analysis revealed that the concentrated HIV co-localized with the cell surface markers HLA-DR, DC-SIGN, and CD86 as well as the tetraspanins CD63, CD9, and CD81. Of these markers, CD81 staining was especially prominent, often with the majority of the total cellular signal concentrated within the structure. The HIV and CD81 remained concentrated over several days of culture, and decay of infectious transmission correlated with loss of compartmentalized HIV over time. Importantly, the compartment lacked early and late endosomal markers as well as the class II peptide-loading molecule HLA-DM, indicating that it was distinct from lysosomal or class II processing vesicles. Recruitment of the compartment to the infectious synapse resulted in exposure of its luminal contents at the cell surface and delivery of both HIV and co-stimulatory molecules to the T-cell surface.

CONCLUSIONS: Based on the staining profile and apparent multilamellar composition, we propose that the compartment is a multivesicular body (MVB) that is normally reserved for sequestration of intact antigens within dendritic cells.

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