Project Details
Projekt
Characterization of the antiviral immunity factor CD317/tetherin
Subject Area
Virology
Term
from 2010 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 163617427
Mammals have evolved a set of intrinsic cellular defense mechanisms capable of inhibiting the replication of viral pathogens. These restriction factors (RFs), which can be constitutively expressed but are frequently up-regulated by host cells in response to virus infection, impose particularly effective barriers in the context of cross-species transmission of viruses. The focus of this project is on the host RF CD317 (also referred to as BST-2/HM1.24/tetherin) that acts late in the HIV replication cycle by potently blocking the release of mature HIV-1 particles from productively infected cells. The activity of CD317 can be antagonized by the HIV-1 protein Vpu and the overall goal of this project is to define the molecular mechanisms of CD317-mediated restriction and its antagonism by HIV-1 Vpu. Our results of the first funding period together with those by other laboratories established that Vpu antagonizes the particle release restriction imposed by CD317 via two mechanisms: (i) impairing overall delivery to the host cell plasma membrane and (ii) altering the submembrane lateral distribution within the plasma membrane for exclusion from viral budding sites. While Vpu helix 2 emerges as a determinant for both Vpu effects, the highly conserved phospho-di-serine motif of Vpu is only involved in the inhibition of CD317 anterograde transport and recycling. In additional preliminary work we identified the host cell protein Arl6IP1 as novel Vpu interactor that enhances the CD317-mediated restriction and established a whole body-tissue microarray-based expression profiling approach to define in situ expression patterns of relevant host factors at physiological sites of HIV transmission. Building on these findings the main goals of the second funding period are (i) the dissection of the molecular mechanisms and host cell ligands employed by Vpu to affect intracellular transport and membrane segregation of CD317, (ii) characterization of the role of the newly identified cellular Vpu interactor Arl6IP1 in HIV-1 restriction, and (iii) the identification of physiologically relevant sites of CD317-and Arl6IP1-mediated restriction ex vivo and in vivo. To address these cardinal questions we will integrate biochemistry, intracellular transport, super-resolution microscopy, virology and immunohistology approaches in the context of the well-established collaboration between our two laboratories. Results of these studies are expected to significantly advance our understanding by which molecular mechanisms and at which physiological sites the interplay between HIV-1 Vpu and CD317 shape HIV-1 pathogenesis.
DFG Programme
Research Grants
