Endothelial Cells Promote Productive HIV Infection of Resting CD4 T Cells by an Integrin-Mediated Cell Adhesion-Dependent Mechanism.

Resting CD4 T cells are primary targets of early HIV infection events , but do not readily support HIV replication . This barrier to infection can be overcome by exposing resting CD4 T cells to endothelial cells (ECs). ECs line blood vessels and direct T cell trafficking into inflamed tissues. Cell trafficking pathways have been shown to have overlapping roles in facilitating HIV replication, but their relevance to EC-mediated enhancement of HIV susceptibility in resting CD4 T cells has not previously been examined. We characterized the phenotype of primary human resting CD4 T cells that became productively infected with HIV when cocultured with primary human blood and lymphatic ECs. The infected CD4 T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4. ICAM-1 and VCAM-1, the cognate ligands for LFA-1 and VLA-4, respectively, were expressed by the ECs in the coculture. Blocking LFA-1 and VLA-4 on resting CD4 T cells inhibited infection by 65.4%-96.9%, indicating that engagement of these integrins facilitates EC-mediated enhancement of productive HIV infection in resting CD4 T cells. The demonstration that ECs influence cellular HIV susceptibility of resting memory CD4 T cells through cell trafficking pathways engaged during the transmigration of T cells into tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.