Cellular entry and uncoating of naked and quasi-enveloped human hepatoviruses

Abstract

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.

TIM1 (HAVCR1): an Essential “Receptor” or an “Accessory Attachment Factor” for Hepatitis A Virus?

“…HAV entry and uncoating remain poorly explained given the exceptional stability of the hepatovirus capsid (8,9). We believe that it is important not to conflate the concepts of attachment factors and receptors for this picornavirus.…”

Intercellular Transmission of Naked Viruses through Extracellular Vesicles: Focus on Polyomaviruses

“…This has been demonstrated for the HAV, Poliovirus, Coxsackievirus, Rhinovirus, or murine Norovirus [ 3 , 10 , 46 ], which suggests that EV membranes get disrupted following endocytosis, possibly by endosomal lipases and lipid extractor proteins. Consistent with this hypothesis, depletion and pharmacological inhibition of the cholesterol transporter Niemann–Pick disease type C1 (NPC1) protein and the lysosomal acid lipase (LAL), significantly impaired EV-associated HAV and HEV but not naked HAV and HEV infection [ 47 , 48 ].…”

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease

“…It has been reported that HCV receptor candidates, such as HAV cellular receptor 1 (HAVcr-1), integrin β1, and gangliosides, are the entry receptor candidates for HAV. Further studies in this vein are needed [ 106 , 107 , 108 ]. Gangliosides seem to function as endosome receptors for infection using both naked and quasi-enveloped HAV virions [ 108 ].…”