A pathogenic picornavirus acquires an envelope by hijacking cellular membranes

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292, USA.
Nature (Impact Factor: 41.46). 03/2013; 496(7445). DOI: 10.1038/nature12029
Source: PubMed


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.

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    • "The recent discovery of membrane-stealing picornaviruses, which now include hepatitis A (Feng et al., 2013), might point to a two-fold strategy for a family of viruses that can leave the host as a non-enveloped virion, as well as maintain a cloaked, enveloped form – at least after infection of certain host cells. Why might a virus utilize this dual strategy? "
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    • "While enteroviruses have historically been considered non-enveloped (i.e., lacking a hostderived membrane bilayer around their capsids) and thus rely on cell lysis to exit, recent reports of extracellular Coxsackievirus B3 (CVB3) being present in vesicles (Robinson et al., 2014) and PV being able to spread non-lytically among host cells (Bird et al., 2014) have raised important questions regarding the extracellular nature of enteroviral particles and the significance of non-lytic exit in the viral life cycle. Moreover hepatitis A, hepatitis E and blue tongue viral particles, all long considered non-enveloped , have been observed surrounded by membranes (Feng et al., 2013; Takahashi et al., 2008; Owens et al., 2004). A central paradigm in virology is that viruses behave as independent infectious units (Flint et al., 2009). "
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    • "Combined with our previous results [10] showing that HCV particles are transported from early to late endosomes/MVB, our current studies suggest that the NS5A-containing HCV particles most likely exit the cells via fusion of MVB to the plasma membrane. Exosomes have been demonstrated to facilitate the budding of human immunodeficiency virus (HIV) [54] and hepatitis A virus (HAV) [55]. Exosome have been known to play important roles in intercellular communications. "
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