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    Involvement of the actin cytoskeleton and small GTPases in the establishment of the virological synapse and the transfer of HIV-1 by intercellular fusion

    Héloïse Leroy

    Wednesday January 27 2021 at 2:30 pm

    Rosalind Franklin room, 2nd floor

    Institut Cochin, 22 rue méchain, Paris 75014

    Supervisors : Jérôme Bouchet et Jérôme Delon

    Team: Signalisation des cellules immunes et Infection rétrovirale

    Department : Infection, Immunity, Inflammation

     

    Abstract:

    Establishing close contacts between HIV-1 target cells facilitates viral infection, as well as evasion of the immune response and antiviral therapy. During my thesis, I was interested in the study of viral transfer by the establishment of virological synapse between T CD4+ lymphocytes or by the establishment of cell fusion phenomena between an infected T CD4+ lymphocyte and macrophages. This latter mechanism of dissemination results in the formation of multinucleated giant cells (MGCs), able of producing large quantities of infectious virus. This type of cell has been observed in vivo in the tissues reservoir of infected patients. My work has allowed to identify certain intracellular mechanisms contributing to these modes of dissemination. Thus, the formation of MGCs and the virological synapse involves reorganization of the actin cytoskeleton in infected and target cells and at the contact area. The study of small GTPases of the Rho family (RhoA, Cdc42, Rac1), regulators of the actin cytoskeleton, allowed me to identify RhoA as a major player in the transfer of HIV-1 by cell fusion. The activity and expression of Rac1, on the other hand, appears to influence the establishment of the virological synapse. Finally, my work on the virological synapse has shown that this mode of viral transfer involves several intracellular trafficking pathways, governed by different Rab GTPases. The endosomal recycling compartment, regulated by Rab11, Rac1 and Fip3 is involved here in the transfer of the virus. Likewise, the endosomal recycling pathways regulated by Rab8, Rab4 and Rab27 appear to contribute to the transfer of HIV-1 by virological synapse between two CD4 + T lymphocytes. The characterization of the intercellular transfer of HIV-1 via these two modes of dissemination could lead us to better understand the pathogenesis of HIV-1 and the formation of viral reservoirs in infected patients.