Aside from the typical retroviral gag, pol, and env genes, HIV-1 encodes a set of accessory proteins. Amongst those, Vpu modulates the expression of several cell surface receptors within the infected cell to promote HIV-1 replication. Particularly, Vpu enhances virus release by overcoming the antiviral action of tetherin. HIV-1 is not the only virus to have evolved countermeasures to inactivate tetherin. Here we have investigated the strategy employed by Kaposi’s sarcoma-associated herpesvirus (KSHV) to escape from tetherin-mediated restriction of virus particle release. We have found that KSHV encodes a ubiquitin ligase, K5, that ubiquitinates tetherin on its cytoplasmic tail to target it for endolysosomal degradation. We then assessed the determinants in the Vpu transmembrane domain required to antagonize tetherin. Three amino acid residues that form one face of the transmembrane region of Vpu were found to be important for the interaction with tetherin. In contrast to Vpu from HIV-1 Group M, those encoded by Group O have not acquired the capacity to counteract tetherin. The defects map to the transmembrane domain and the membrane-proximal hinge region of the first alpha helix of the cytoplasmic tail; both are respectively defective for tetherin binding and trans-Golgi network-associated subcellular localization. As the panel of Vpu’s targets is increasing, we have collaborated with Paul Lehner’s group to identify new cellular substrates of Vpu. The glutamine transporter, SNAT-1, was identified by proteomic screening (SILAC). SNAT-1 is downregulated and degraded in HIV-1 infected CD4+ T cells. We are currently investigating the effects of Vpu-mediated SNAT-1 degradation and glutamine limitation on virus growth and cell proliferation/survival in primary CD4+ infected T cells. In parallel, we have investigated the molecular mechanism by which Vpu achieves SNAT-1 depletion.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:631312 |
| Date | January 2013 |
| Creators | Vigan, Raphael |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/cellular-targets-of-hiv1-vpu(14764437-266c-4b94-b53e-1a7a7e6ea2a9).html |
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