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 in vivo, but do not readily support HIV replication in vitro. This barrier to infection can be overcome by exposing resting CD4+ T cells to endothelial cells. Endothelial cells 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 endothelial cell-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 co-cultured with primary human blood and lymphatic endothelial cells. 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 endothelial cells in the co-culture. 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 endothelial cell-mediated enhancement of productive HIV infection in resting CD4+ T cells. The demonstration that endothelial cells 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.  .