Many 'non-enveloped' viruses, including hepatitis A virus (HAV), are released non-lytically from infected cells as infectious, quasi-enveloped virions cloaked in host membranes. Quasi-enveloped HAV (eHAV) mediates stealthy cell-to-cell spread within the liver, whereas stable naked virions shed in feces are optimized for environmental transmission. eHAV lacks virus-encoded surface proteins, and how it enters cells is unknown. We show both virion types enter by clathrin- and dynamin-dependent endocytosis, facilitated by integrin β1, and traffic through early and late endosomes. Uncoating of naked virions occurs in late endosomes, whereas eHAV undergoes ALIX-dependent trafficking to lysosomes where the quasi-envelope is enzymatically degraded and uncoating ensues coincident with breaching of endolysosomal membranes. Neither virion requires PLA2G16, a phospholipase essential for entry of other picornaviruses. Thus naked and quasi-enveloped virions enter via similar endocytic pathways, but uncoat in different compartments and release their genomes to the cytosol in a manner mechanistically distinct from other Picornaviridae.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data tables have been provided for Figures 1-5 and Supplementary Figures S1-S5.
- Stanley M Lemon
- Stanley M Lemon
- Efraín E Rivera-Serrano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Wesley I Sundquist, University of Utah School of Medicine, United States
© 2019, Rivera-Serrano et al.
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