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 membrane1, 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 hepatitis2–4. HAV infects in a stealth-like manner and replicates efficiently in the liver5. Virus-specific antibodies appear only after 3–4 weeks of infection, and typically herald its resolution3,4. Although unexplained mechanistically, both anti-HAV antibody and inactivated whole-virus vaccines prevent disease when administered as late as 2 weeks after exposure6, when virus replication is well established in the liver5. 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 exosomes7, small vesicles that are increasingly recognized to play important roles in intercellular communications. They are fully infectious, sensitive to chloroform extraction, and circulate in the blood of infected humans. Their biogenesis is dependent upon host proteins associated with endosomal-sorting complexes required for transport (ESCRT)8, VPS4B and ALIX. While the hijacking of membranes by HAV facilitates escape from neutralizing antibodies and likely promotes virus spread within the liver, anti-capsid antibodies restrict replication following infection with eHAV, suggesting a possible explanation for post-exposure prophylaxis. Membrane hijacking by HAV blurs the classic distinction between “enveloped” and “nonenveloped” viruses, and has broad implications for mechanisms of viral egress from infected cells as well as host immune responses.

Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection

“…HCV utilizes many receptors in vitro, including the low-density lipoprotein receptor ( Dreux et al, 2012;Feng et al, 2013;Ramakrishnaiah et al, 2013).…”

“…Supporting this hypothesis, HPgV RNA-containing microvesicles positive for an exosomal marker (cellular CD63) were able to deliver viral RNA to uninfected PBMCs and viral RNA replicated within these cells ex vivo (Chivero et al, 2014). Other viruses such as hepatitis A virus and HCV have also been shown to utilize exosomes for viral transmission and intercellular communication (Bukong et al, 2014;Dreux et al, 2012;Feng et al, 2013;Ramakrishnaiah et al, 2013).…”

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

“…However, recent findings pertaining to 2 other nonenveloped enteric viruses, hepatitis A virus (HAV) and hepatitis E virus (HEV), demonstrate a unique mode of viral egress in which classically nonenveloped viruses can be released from cells wrapped in cellular envelopes. 26,27 It is interesting to speculate that NoVs utilize a similar strategy to exit infected B cells in the absence of cell lysis. The difference in cytopathicity between M12 cells and other cell lines (e.g., RAW264.7, WEHI-231) may reflect differential cellular regulation of cytopathic versus noncytopathic NoV infection and could thus represent a useful tool in future studies probing putative alternate forms of viral egress.…”

Extracellular vesicles and viruses: Are they close relatives?

“…Especially in the case of retroviruses, EVs generated in infected cells contain selected molecules of viral origin (4) and can be so similar to noninfectious defective viruses that have lost their ability to replicate that the difference between them becomes blurred. In other cases, EVs provide an "envelope" to nonenveloped viruses, e.g., hepatitis A, and these EV-encapsulated viruses can infect cells (5). Similarly, EV released by hepatitis C-infected cells can carry fully infectious viral genomes that in target cells generate new infectious viral particles (6).…”