Host mature tRNAome as a decoding switch regulates antiviral and proviral responses

Current virus-host studies primarily concentrate on the battle race at the levels of mRNA transcription and protein translation. These processes, on both the host and virus sides, rely on the mature tRNAome to decode, yet they remain largely unexplored. In this study, we report a previously unrecognized dichotomy in the host tRNAome concerning antiviral and proviral responses. We demonstrate that the host’s mature tRNAome, which is coupled with amino acid metabolism, is dynamically remodeled by interferon-alpha (IFN-α) and regulates the translation efficiencies of downstream interferon-stimulated genes (ISGs). Interference with tRNAome maturation or charging dampens the antiviral efficacy of IFN-α in hepatitis E virus (HEV)-infected cells. In contrast, hepatitis B virus (HBV) infection, which does not induce the ISG response, still remodels the host tRNAome to promote its own infection, particularly through tRNA-Arg-UCU. Both charging and genetic interference with tRNA-Arg-UCU inhibit HBV DNA replication, while its overexpression in vitro and in a male mouse model enhances HBV DNA replication and translation. Importantly, this tRNA not only facilitates the decoding of the nucleocapsid, where HBV replication initiates, but also indirectly affects pregenomic RNA (pgRNA) transcription, which encodes the nucleocapsid subunit, core protein. These findings suggest the potential for tRNA-based strategies to amplify the interferon response and develop antivirals targeting HBV. The role of the tRNAome in virus-host interaction is poorly understood. Here, the authors report a dual role of the host tRNAome showing that it is remodeled by IFN-α to regulate antiviral defenses, yet can be exploited by hepatitis viruses to benefit infection, particularly when host antiviral responses are not induced.