CD317 functions as a key antiviral factor in human herpesvirus 6 (HHV-6) infection.

CD317, an interferon-stimulated gene, is known for its role in inhibiting the release of various enveloped viruses from infected cells. However, its function can vary, as it also promotes infection in certain contexts, such as with human cytomegalovirus (HCMV). Human herpesvirus 6 (HHV-6) and HCMV are both classified within the β-herpesvirus subfamily. The role of CD317 in HHV-6 infection has not been previously investigated. In this study, we found that (i) HHV-6 infection induces CD317 expression, which in turn restricts HHV-6 infection, (ii) type I interferon stimulation induces CD317 expression, thereby inhibiting HHV-6 infection, (iii) the HHV-6 envelope glycoprotein O (gO) interacts with CD317, leading to gO degradation, and (iv) CD317 is incorporated into HHV-6 virions. This work represents the first report elucidating the role of CD317 in HHV-6 infection and reveals a novel function of gO in this process. IMPORTANCE: Upon stimulation with type I interferon, hundreds of interferon-stimulated genes (ISGs) are induced to express. For an individual virus, it is crucial to identify and analyze the key ISGs. Here, we discovered that CD317 is one of the key ISGs that restrict HHV-6 infection. While CD317 is well known for its ability to inhibit the release of progeny virions, we have revealed a novel role for CD317 in restricting HHV-6 infection by inhibiting viral entry. Additionally, we found that CD317 interacts with HHV-6 glycoprotein O (gO), a protein of unknown function, leading to the proteasomal degradation of gO. This finding may provide valuable clues for further analysis of gO's function.