Vpu protects HIV-infected cells from antibody-dependent cellular phagocytosis by counteracting tetherin.

Abstract

Tetherin is an interferon-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. HIV-1 Vpu counteracts this restriction by removing tetherin from sites of virus release. Accordingly, Vpu mutations that disrupt tetherin antagonism increase Env accumulation on the surface of HIV-infected cells. We found that Vpu mutations that impair tetherin antagonism also increase the susceptibility of HIV-infected cells to antibody-dependent cellular phagocytosis (ADCP). Increased sensitivity to ADCP was lost in tetherin-knockout cells and conditionally restored by doxycycline-inducible tetherin. Thus, Vpu protects HIV-infected cells from ADCP by preventing virion accumulation on the cell surface, similar to its protection against antibody-dependent cellular cytotoxicity (ADCC). By serving as a link between innate and adaptive immunity, the antiviral activity of tetherin may be amplified in vivo by Fc-mediated antibody effector functions and therefore much greater than initially appreciated based solely on its ability to inhibit virus release in cell culture assays.