Unconventional secretion of hepatitis A virus

In virology lectures, students learn the classifications: viruses have either RNA or DNA genomes; they are released either by killing the infected cell or by budding harmlessly from it; viral particles are either “enveloped” or “nonenveloped.” In cell biology classes, students learn the topology of cell membranes: cytoplasmic proteins are synthesized by cytosolic ribosomes, and proteins destined for secretion contain signal sequences that allow endoplasmic reticulum (ER)-associated ribosomes to direct them into the lumen within the ER. Then, secretion of these luminal contents proceeds via the Golgi apparatus and exocytic vesicles to the outside of the cell. Of course, such classifications beg to be violated, and in PNAS, McKnight et al. (1) consolidate a mechanism by which hepatitis A virus (HAV) does just that. Nonenveloped or, more colorfully, “naked” viruses such as HAV and other picornaviruses (small RNA viruses) are cytoplasmic particles that contain only the genomic nucleic acid and complexed proteins. This has several consequences: for example, proteinaceous coats are often more stable to environmental insult than viral envelopes. Thus, picornaviruses such as HAV, poliovirus, and norovirus are famously stable in water, from whence they readily infect humans via oral–fecal transmission. Another consequence of this nonenveloped structure is that it should be logical that viral exit should require leakage of cytoplasm through a ruptured plasma membrane, thus killing the cell. It has long been noted, however, that natural isolates of HAV do not appear to lyse infected cells in cultured cells or in infected people (reviewed in refs. 2 and 3). In liver biopsies of some patients, a large proportion of cells contain infectious virus, yet no cell death is evident. During acute human infection, infectious HAV particles appear in feces before any evidence of any immune-mediated hepatocyte damage occurs. Thus, it was hypothesized that the …