Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producer cells assists de novo infection by enhancing viral gene expression

Viruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, secrete extracellular vesicles such as exosomes containing proteins and miRNAs. These vesicles mediate intercellular communications, suggesting that they modulate viral infection by adapting cellular conditions. However, the roles of exosomes in viral infection remain unclear. Here we screened viral proteins to identify those responsible for the exosome-mediated upregulation of Epstein-Barr virus (EBV) infection. We found BGLF2 protein encapsulated in exosomes, which enhanced the EBV infection of Akata(-) B-cells. BGLF2 protein is a tegument protein that lines the space between the envelope and the nucleocapsid, and it is released shortly after infection into the cytoplasm. Therefore, tegument protein BGLF2 is encapsulated not only in viral particles, but also in exosomes secreted from infected cells, and plays crucial roles in establishing the EBV latent infection by modulating the cellular environment. ImportanceTegument proteins that line the space between the envelope and nucleocapsid are released shortly after infection into the cytoplasm to modulate the cellular environment. In this study, we identified that tegument protein BGLF2, which is conserved in all herpesviruses, is incorporated into exosomes and transferred to neighboring cells. Exosomes containing BGLF2 enhanced the infectivity of EBV. These findings suggest that this and perhaps other tegument proteins support viral infection not only between the envelope and nucleocapsid, but also in extra-virus particles such as exosomes.