| Cell-to-cell transmission of human immunodeficiency virus-1 (HIV-1) occurs via the virological synapse (VS), a tight cell-cell junction formed between an HIV-infected cell and target cell in which the HIV-1-infected cell polarizes and releases virions towards the non-infected target cell. In this dissertation I focus on the characterization of the HIV-1 envelope gp120-induced virological synapse and its effect on the target T cell.;HIV-1 gp120-presenting surfaces induce the formation of a VS, which is characterized by segregated supramolecular structures with a central supramolecular activation complex of envelope (cSMAC) surrounded by a ring of LFA-1-ICAM-1 interactions (pSMAC). Furthermore, HIV-1 gp120 interaction with its receptors is initially organized into microclusters that undergo F-actin-dependent consolidation into a cSMAC. Src kinases are active in both gp120 microclusters and in the VS cSMAC. The early TCR signaling machinery is only partially activated at the VS, and therefore signaling does not propagate to trigger Ca2+ elevation or increase CD69 expression. However, these partial TCR signals act locally to create an F-actin-depleted zone. I propose a model in which the F-actin-free zone formed within the target CD4 T cell enhances the reception of virions by releasing the physical barrier for HIV-1 entry and facilitating post-entry events. |
