| Abstract: | ![]()
Tetherin is an IFN-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. HIV-1 overcomes this restriction factor by expressing HIV-1 viral protein U (Vpu), which down-regulates and degrades tetherin. We report that mutations in Vpu that impair tetherin antagonism increase the susceptibility of HIV-infected cells to antibody-dependent cell-mediated cytotoxicity (ADCC), and conversely that RNAi knockdown of tetherin, but not other cellular proteins down-modulated by Vpu, decreases the susceptibility of HIV-infected cells to ADCC. These results reveal that Vpu protects HIV-infected cells from ADCC as a function of its ability to counteract tetherin. By serving as link between innate and adaptive immunity, the antiviral activity of tetherin may be augmented by virus-specific antibodies, and hence much greater than previously appreciated.Under conditions of IFN induction, tetherin is rapidly up-regulated on the surface of infected cells and prevents virus release by physically bridging nascent virions to the cell membrane (1–3). This activity can be explained by the unusual topology of tetherin, which includes an N-terminal transmembrane domain and a C-terminal glycosyl-phosphatidylinositol tail that allow both ends of the molecule to be anchored in lipid membranes (4). Although tetherin was initially identified as the cellular gene product that accounts for a late-stage defect in the release of vpu-deleted HIV-1 from restrictive cells (5, 6), it is now recognized to have antiviral activity against diverse families of enveloped viruses (7–11).The primate lentiviruses have evolved to use at least three different viral proteins to counteract restriction by tetherin. Whereas most simian immunodeficiency viruses (SIVs) use Nef to counteract the tetherin proteins of their nonhuman primate hosts (12–14), HIV-1 and HIV-2 use their Vpu and Env proteins, respectively, to counteract human tetherin because of the absence of sequences in the cytoplasmic domain of the protein required for susceptibility to Nef (5, 6, 15). Tetherin has therefore had a significant impact on shaping the course of lentiviral evolution in primates.Tetherin can inhibit retroviral replication in vivo as revealed by an IFN-dependent effect on the suppression of murine leukemia virus in WT, but not tetherin-deficient, mice (16). Instances of lentiviral adaptation to tetherin, including the acquisition of compensatory changes in gp41 of a nef-deleted strain of SIV passaged in rhesus macaques (17), and changes that restore the anti-tetherin activity of Nef in HIV-1–infected chimpanzees (18), further underscore the importance of tetherin antagonism for efficient virus replication in vivo. However, under certain circumstances, tetherin can also facilitate virus replication by enhancing cell-to-cell transmission (19). Indeed, a role for tetherin in promoting cell-to-cell transmission probably accounts for the selection of vpu-deficient HIV-1 under cell culture conditions designed to mimic rapid T-cell turnover (20). Thus, although the net effect of tetherin on virus replication in infected hosts is antiviral, the immunological mechanisms underlying this antiviral activity are not fully understood.By using an assay designed to measure the ability of antibodies to direct the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) (21), we show that Vpu protects HIV-infected cells from elimination by ADCC. We further demonstrate that this protection reflects the role of Vpu in counteracting restriction by tetherin. These results imply that tetherin enhances the susceptibility of HIV-infected cells to antibodies, thereby revealing an unappreciated link between innate and adaptive immunity. These results also suggest that the antiviral activity of tetherin may be augmented by virus-specific antibodies, and hence may be much greater than previously appreciated based solely on its ability to suppress virus replication in cell culture. |
