Advertisement

 

 

LFA-1 engagement triggers T cell polarization at the HIV-1 virological synapse.

LFA-1 engagement triggers T cell polarization at the HIV-1 virological synapse.
Author Information (click to view)

Starling S, Jolly C,


Starling S, Jolly C, (click to view)

Starling S, Jolly C,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

Journal of virology 2016 8 24() pii

Abstract

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.

IMPORTANCE
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.

Submit a Comment

Your email address will not be published. Required fields are marked *

eight − two =

[ HIDE/SHOW ]