Herpes Simplex Virus 1 Counteracts Tetherin Restriction via Its Virion Host Shutoff Activity

Helen L Zenner,Rui Mauricio,George Banting,Colin M Crump

doi:10.1128/jvi.02167-13

Helen L Zenner, Rui Mauricio + Show 2 more

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https://doi.org/10.1128/jvi.02167-13

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Abstract

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 restriction appear to be those that acquire their envelopes at the plasma membrane, although many 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 shutoff 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.

Highlights

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
We investigated two main questions: (i) does tetherin restrict herpes simplex virus 1 (HSV-1) release from infected cells? and (ii) is tetherin an important target of virion host shutoff protein (Vhs) activity? Our data demonstrate the following: tetherin expression inhibits the release of HSV-1, wildtype HSV-1 efficiently blocks tetherin expression, and Vhs activity is important for HSV-1 to evade tetherin restriction
To examine the effect of tetherin expression on HSV-1 release, we determined the amount of infectious virus released into culture supernatant compared to the amount that remained cell associated using COS-7 cells expressing HA-tagged versions of wildtype human tetherin or human tetherin lacking the C-terminal GPI anchor, which is unable to restrict virus release

Summary

Introduction

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. Tetherin’s antiviral function is likely to be more than just a physical method of restricting virus release from the cell surface, with internalization and degradation of virions as well as activation of proinflammatory gene expression via NF-␬B potentially contributing to tetherin-mediated defense against virus infection [6, 7]. Studies with tetherin knockout mice have demonstrated that tetherin is important for the restriction of murine leukemia virus replication and disease in vivo, confirming its role as a bona fide antiviral factor [16] Studies with another knockout mouse have shown that tetherin deletion inhibits alpha interferon (IFN-␣) secretion in response to HSV-1 or mouse cytomegalovirus infection [17], suggesting a role for tetherin in sensing/responding to herpesviruses in vivo.

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