Herpes simplex virus 1 counteracts tetherin restriction via its virion host shutoff activity

The interferon-inducible membrane protein tetherin (Bst-2, or CD317) is an antiviral factor that inhibits enveloped virus release by cross-linking newly formed virus particles to the producing cell. The majority of viruses that are sensitive to tetherin restric-tion appear to be those that acquire their envelopes at the plasmamembrane, althoughmany viruses, including herpesviruses, envelope at intracellular membranes, and the effect of tetherin on such viruses has been less well studied. We investigated the tetherin sensitivity and possible countermeasures of herpes simplex virus 1 (HSV-1). We found that overexpression of tetherin inhibits HSV-1 release and that HSV-1 efficiently depletes tetherin from infected cells. We further show that the virion host shut-off protein (Vhs) is important for depletion of tetherin mRNA and protein and that removal of tetherin compensates for defects in replication and release of a Vhs-null virus. Vhs is known to be important for HSV-1 to evade the innate immune response in vivo. Taken together, our data suggest that tetherin has antiviral activity toward HSV-1 and that the removal of tetherin by Vhs is important for the efficient replication and dissemination of HSV-1. Tetherin (Bst-2, or CD317) is an interferon (IFN)-induciblemembrane glycoprotein that has been shown to have potent antiviral activity by inhibiting the release of many enveloped vi-ruses (1, 2). Tetherin has an unusual topology with a short N-ter-minal cytoplasmic domain followed by a transmembrane domain, an extracellular loop, and a C-terminal glycosylphosphatidylino