HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS) where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill-defined. Here we have used a reductionist bead-coupled antibody assay as a model of the VS and show that cross-linking the integrin LFA-1 is alone sufficient to induce active T cell polarization and recruitment of the MTOC in HIV-1 infected cells. Mutant cell lines coupled with inhibitors demonstrated that LFA-1 induced polarization was dependent on the T cell kinase ZAP70. Notably, immunofluorescence staining of viral proteins revealed an accumulation of surface Env at sites of LFA-1 engagement with intracellular Env localized to a Golgi-compartment proximal to the polarized MTOC. Furthermore, blocking LFA-1 induced MTOC polarization through ZAP70 inhibition prevented intracellular Env polarization. Taken together these data reveal that LFA-1 is a key determinant in inducing dynamic T cell remodeling to the VS and suggest a model in which LFA-1 engagement triggers active polarization of the MTOC and the associated Env-containing secretory apparatus to sites of cell-cell contact to support polarized viral assembly and egress for efficient cell-cell spread.
HIV-1 causes AIDS by spread within immune cells and depletion of CD4 T lymphocytes. Rapid spread between these cells occurs by highly efficient cell-cell transmission that takes place at the Virological Synapse (VS). VS are characterized by striking T cell remodeling that is spatially associated with polarized virus assembly and budding at sites of cell contact. Here we show that the integrin LFA-1 triggers organelle polarization and viral protein recruitment, facilitating formation of the VS and that this requires the T cell kinase ZAP70. Taken together, these data suggest a mechanism for how HIV-1 infected T cells sense and respond to cell contact to polarize viral egress and promote cell-cell spread. Understanding how cell-cell spread is regulated may help reveal therapeutic targets to specifically block this mode of HIV-1 dissemination.