title: A pathogenic picornavirus acquires an envelope by hijacking cellular membranes.
abstract: Animal viruses are broadly categorized structurally by the presence or absence of an envelope composed of a lipid-bilayer membrane, attributes that profoundly affect stability, transmission and immune recognition. Among those lacking an envelope, the Picornaviridae are a large and diverse family of positive-strand RNA viruses that includes hepatitis A virus (HAV), an ancient human pathogen that remains a common cause of enterically transmitted hepatitis. HAV infects in a stealth-like manner and replicates efficiently in the liver. Virus-specific antibodies appear only after 3-4 weeks of infection, and typically herald its resolution. Although unexplained mechanistically, both anti-HAV antibody and inactivated whole-virus vaccines prevent disease when administered as late as 2 weeks after exposure, when virus replication is well established in the liver. Here we show that HAV released from cells is cloaked in host-derived membranes, thereby protecting the virion from antibody-mediated neutralization. These enveloped viruses ('eHAV') resemble exosomes, small vesicles that are increasingly recognized to be important in intercellular communications. They are fully infectious, sensitive to extraction with chloroform, and circulate in the blood of infected humans. Their biogenesis is dependent on host proteins associated with endosomal-sorting complexes required for transport (ESCRT), namely VPS4B and ALIX. Whereas the hijacking of membranes by HAV facilitates escape from neutralizing antibodies and probably promotes virus spread within the liver, anti-capsid antibodies restrict replication after infection with eHAV, suggesting a possible explanation for prophylaxis after exposure. Membrane hijacking by HAV blurs the classic distinction between 'enveloped' and 'non-enveloped' viruses and has broad implications for mechanisms of viral egress from infected cells as well as host immune responses.
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292, USA.
authors.forename: Zongdi
authors.initials: Z
authors.lastname: Feng
authors.forename: Lucinda
authors.initials: L
authors.lastname: Hensley
authors.forename: Kevin L
authors.initials: KL
authors.lastname: McKnight
authors.forename: Fengyu
authors.initials: F
authors.lastname: Hu
authors.forename: Victoria
authors.initials: V
authors.lastname: Madden
authors.forename: Lifang
authors.initials: L
authors.lastname: Ping
authors.forename: Sook-Hyang
authors.initials: SH
authors.lastname: Jeong
authors.forename: Christopher
authors.initials: C
authors.lastname: Walker
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lanford
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006506:Hepatitis A / Q000097:blood / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D030041:Hepatitis A virus / Q000737:chemistry / Q000254:growth & development / Q000276:immunology / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008099:Liver / Q000821:virology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D002679:Pan troglodytes; D014759:Viral Envelope Proteins
chemical_list: D057134:Antibodies, Neutralizing; D056827:Endosomal Sorting Complexes Required for Transport; D014759:Viral Envelope Proteins
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