Hepatoviruses, Extracellular Vesicles, and the Concept of Enveloped Versus Nonenveloped Viruses.

A common cause of acute hepatitis in humans, hepatitis A virus (HAV) replicates within hepatocytes without inducing cytopathology. Virus is released from infected cells in the absence of cell lysis as quasi-enveloped HAV (eHAV) virions cloaked in host membranes. These virions circulate in blood when exported across the basolateral membrane of hepatocytes but are stripped of their membranes by bile salts when exported across the apical membrane into the biliary system resulting in fecal shedding of abundant naked, nonenveloped virus. This review summarizes the composition and structure of these two distinct types of infectious extracellular hepatovirus virions and outlines the evidence for specific signals within HAV capsid proteins that mediate interactions with the endosomal sorting complexes required for transport (ESCRT). Capsid protein interactions with the ESCRT-associated proteins ALIX and HD-PTP play a crucial role in the budding of newly assembled capsids into multivesicular endosomes, the first step in nonlytic release of quasi-enveloped virions from infected cells. This review also considers how eHAV virions enter naïve cells to establish infection in the absence of a virally encoded protein on their surface and compares the role played by quasi-envelopment in the hepatovirus life cycle with the nonlytic release of other types of viruses in extracellular vesicles.