Hepatitis E virus polymerase binds to IFIT1 to protect the viral RNA from IFIT1-mediated translation inhibition

Hepatitis E virus (HEV) induces interferons and regulates the induction of interferon-stimulated genes (ISGs) in the host cell. HEV infection has been shown to promote the expression of different ISGs, such as ISG15, IFIT1, MX1, RSAD2/Viperin and CxCL10, in cell culture and animal models. Interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) is an ISG-encoded protein that inhibits the translation of viral RNA, having 5'-triphosphate or the mRNA lacking 2'-O-methylation on the 5'cap. In this study, we found that IFIT1 binds to HEV RNA to inhibit its translation. HEV replication is also restricted in hepatoma cells with overexpressed IFIT1. However, despite this binding of IFIT1 to HEV RNA, HEV successfully replicates in hepatoma cells in the infection scenario. In an effort to identify the underlying mechanism, we found that HEV RNA-dependent RNA polymerase (RdRp) binds to IFIT1, thereby protecting the viral RNA from IFIT1-mediated translation inhibition. RdRp sequesters IFIT1, resulting in the successful progression of viral replication in the infected cells. Thus, we discovered a distinct pro-viral role of HEV RdRp that is crucial for successful infection in the host, and propose a unique mechanism developed by HEV to overcome IFIT1-mediated host immune response.