Human Herpesvirus‐6 Induces MVB Formation, and Virus Egress Occurs by an Exosomal Release Pathway

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Abstract
The final envelopment of most herpesviruses occurs at Golgi or post‐Golgi compartments, such as the trans Golgi network (TGN); however, the final envelopment site of human herpesvirus 6 (HHV‐6) is uncertain. In this study, we found novel pathways for HHV‐6 assembly and release from T cells that differed, in part, from those of alphaherpesviruses. Electron microscopy showed that late in infection, HHV‐6‐infected cells were larger than uninfected cells and contained many newly formed multivesicular body (MVB)‐like compartments that included small vesicles. These MVBs surrounded the Golgi apparatus. Mature virions were found in the MVBs and MVB fusion with plasma membrane, and the release of mature virions together with small vesicles was observed at the cell surface. Immunoelectron microscopy demonstrated that the MVBs contained CD63, an MVB/late endosome marker, and HHV‐6 envelope glycoproteins. The viral glycoproteins also localized to internal vesicles in the MVBs and to secreted vesicles (exosomes). Furthermore, we found virus budding at TGN‐associated membranes, which expressed CD63, adaptor protein (AP‐1) and TGN46, and CD63 incorporation into virions. Our findings suggest that mature HHV‐6 virions are released together with internal vesicles through MVBs by the cellular exosomal pathway. This scenario has significant implications for understanding HHV‐6’s maturation pathway.