Mechanisms of cell motility inhibition by the HIV-1 pathogenesis factor NEF

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The NEF protein is a virally encoded pathogenesis factor of Human Immunodeficiency Viruses (HIV) that promotes virus replication and immune evasion of virus producing cells in the infected host. We previously identified inhibition of host cell motility as a highly conserved biological property of NEF and established inhibition of actin remodeling as a molecular mechanism that is necessary but not sufficient for this activity. The aim of this proposal is to define the actin-independent activities NEF employs to modulate cell motility. This will be achieved by combining in vivo analyses of NEF- expressing zebrafish primordial germ cells (PGC) with ex vivo studies of virally infected primary human T lymphocytes and macrophages. Advanced real time imaging approaches will provide detailed characterization of the defects induced by NEF on a single cell level and will be directly coupled to quantification of cell motility. Concomitant genetic and biochemical analyses are designed to unravel the underlying molecular mechanisms. Together these interdisciplinary studies will employ NEF as a valuable tool to decipher basic principles of PGC migration and are expected to yield important insights into the mechanism and patho-physiological impact on host cell motility.