Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins

•Tetherin restricts the release of HSV-2 virus particle.•HSV-2 infection downregulates the expression of tetherin.•Multiple HSV-2 glycoproteins contribute to the downregulation of tetherin.•HSV2 glycoproteins gB, gD, gH, and gL physically interact with tetherin.

Tetherin has been defined as a restriction factor of HIV-1 and several other enveloped viruses. However, the significance of tetherin in viral infection remains to be further addressed. Here, we investigated whether tetherin plays a role in HSV-2 infection. Our study revealed that overexpression of tetherin restricted the release of HSV-2 into the extracellular medium, while knockdown of tetherin by siRNA enhanced its release. We further demonstrated that HSV-2 infection and viral glycoproteins gB, gD, gH and gL but not gM significantly downregulated the endogenous expression of tetherin. Additional study indicated that tetherin likely physically interacted with gB, gD, gH and gL. This is the first time that tetherin has been shown to be counteracted by multiple viral components of a virus. Our findings inform the complexity of HSV-2-host interactions, providing basis for understanding the role of tetherin as a viral restriction factor and the mechanisms underlying viral countermeasures.