Starling, SL; (2016) Molecular characterisation of the HIV-1 virological synapse. Doctoral thesis , UCL (University College London).

Abstract

Direct cell-cell spread of HIV-1 between CD4+ T cells confers many advantages for the virus including more rapid infection kinetics, evasion of neutralising antibodies and components of antiretroviral therapy, potentially posing a barrier to HIV-1 eradication. Cell-cell spread occurs at virus-induced intercellular contacts called Virological Synapses (VS). VS are characterised by dynamic T cell remodelling and serve as hot-spots for polarized HIV-1 assembly and budding. It is increasingly apparent that HIV-1 infected T cells can sense and respond to cell-cell contact to support efficient VS formation and viral spread; however the receptor triggers for contact-induced polarisation at the VS are unknown. The aims of this project were to: 1) investigate plasma membrane triggers of polarisation in HIV-1 infected T cells; 2) interrogate cell-contact induced T cell signalling pathways; and 3) determine the consequences for HIV-1 dissemination between T cells. The results obtained have revealed that T polarisation at the VS is triggered by engagement of the integrin LFA-1 on HIV-1 infected T cells and that LFA-1 alone was sufficient to induce active, microtubule-dependent polarisation in HIV-1 infected T cells. It has also been shown that T cell adaptor protein ZAP70, but not SLP-76 is required for LFA-1 induced responses, suggestive of activation of intracellular signalling at the VS. Further analysis of the T cell signalling machinery has demonstrated that the kinase Lck is also required for synapse formation and efficient HIV-1 cell-cell spread. We conclude that polarisation at the VS proceeds through an intracellular pathway initiated by receptor-mediated activation of T cell signalling that in turn regulates HIV-1 spread between T cells. These results in this thesis have further revealed similarities between VS and related immunological synapses. This work will help to inform a deeper understanding of HIV-1 cell-cell dissemination, pathogenesis and T cell biology, potentially aiding future therapeutic design.

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