Naked Viruses That Aren't Always Naked: Quasi-Enveloped Agents of Acute Hepatitis

Abstract

Historically, viruses were considered to be either enveloped or nonenveloped. However, recent work on hepatitis A virus and hepatitis E virus challenges this long-held tenet. Whereas these human pathogens are shed in feces as naked nonenveloped virions, recent studies indicate that both circulate in the blood completely masked in membranes during acute infection. These membrane-wrapped virions are as infectious as their naked counterparts, although they do not express a virally encoded protein on their surface, thus distinguishing them from conventional enveloped viruses. The absence of a viral fusion protein implies that these quasi-enveloped virions have unique mechanisms for entry into cells. Like true enveloped viruses, however, these phylogenetically distinct viruses usurp components of the host ESCRT system to hijack host cell membranes and noncytolytically exit infected cells. The membrane protects these viruses from neutralizing antibodies, facilitating dissemination within the host, whereas nonenveloped virions shed in feces are stable in the environment, allowing for epidemic transmission.

Protein composition of the hepatitis A virus quasi-envelope

“…Whereas 11 were of indeterminate origin, peptide sequences of the The red brackets indicate fractions that were pooled with fractions of similar density from gradients loaded with supernatant fluids from noninfected cells maintained in the opposing media and subjected to mass spectrometry. ○, HAV RNA; GEs (genome equivalents) per 20 μL; ♦, density (g/cm 3 ). (B) Distribution of isotopic enrichment in peptides identified in a search against the human UniProt database in the four independently 13 C-labeled (Left) and 12 C-labeled (Right) eHAV samples submitted for mass spectrometry in experiments 1 (Top) and 2 (Bottom).…”

“…Recent studies have brought increasing recognition to the fact that multiple members of the Picornaviridae are released from cells enclosed in membranous vesicles in the absence of cell lysis (2)(3)(4)(5)(6). This mode of cellular egress has been suggested to play an important role in disease pathogenesis by masking viral antigens from the immune system (2) or increasing the number of viral genomes delivered to single infected cells (6).…”

“…This indicates that nonstructural HAV proteins are not copackaged with capsids in eHAV vesicles, although they are likely present at high local abundance within the cellular compartment(s) in which the viral RNA replicates and the capsid assembles. ALIX-VP2 capsid protein interactions likely play a major role in this sorting process, although other, yet-to-be-determined sorting mechanisms may well be operative (2,3).…”

“…eHAV virions have been identified in sera collected from persons with acute hepatitis A, as well as in supernatant fluids of infected cell cultures. These virions are completely cloaked in host-derived membranes that protect the capsid from neutralizing antibody until the quasi-envelope is degraded within an endosomal compartment (2,3). Nevertheless, they have specific infectivity similar to naked, nonenveloped HAV particles in cell culture.…”

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.…”