Molecular biology

VIRION

Non-enveloped, spherical, about 30 nm in diameter, composed of a protein shell surrounding the naked RNA genome. The capsid consists of a densely-packed icosahedral arrangement of 60 protomers, each consisting of 3 polypeptides, VP1, VP2, and VP3. VP4 does not seem to be incorporated into virions.

GENOME

Monopartite, linear, ssRNA(+) genome of 7.478 kb, polyadenylated, composed of a single ORF encoding a polyprotein. Viral genomic RNA has a viral protein (VPg) at its 5’ end instead of a methylated nucleotide cap structure. The long UTR at the 5’ end contains an internal ribosome entry site (IRES) type III. The P1 region encodes the structural polypeptides. The P2 and P3 regions encode the nonstructural proteins associated with replication. Encodes a unique protease 3C. The shorter 3’ UTR is polyadenylated and is important in (-)strand synthesis.

GENE EXPRESSION

The virion RNA is infectious and serves as both the genome and viral messenger RNA. The IRES allows direct translation of the polyprotein. The polyprotein is initially processed by the viral protease into three precursor proteins, P1, P2, and P3. Precursor P1 is then proteolytically cleaved to yield the structural proteins. Precursors P2 and P3 are processed into replicase, VPg, and a number of proteins that modify the host cell, ultimately leading to cell lysis. Unlike other picornaviruses, HAV needs the eIF4G factor for the initiation of translation and thus cannot shut down host protein synthesis. HAV displays highly deoptimized codon usage. The resulting slow translation rate probably contributes to the high stability of viral capsid and may play a role in escaping to host cell defenses.

REPLICATION

CYTOPLASMIC

1. Virus attaches to host receptors, inducing a capsid conformational change.
2. The capsid opens a pore in the host cell membrane, and the viral genomic RNA penetrates into the host cell cytoplasm.
3. VPg is removed from the viral RNA, which is then translated into a processed polyprotein.
4. Replication of viral RNA takes place on membrane vesicles derived from the ER. A negative-sense complementary ssRNA is synthesized using the genomic RNA as a template.
5. New genomic RNA synthesized using the negative-sense RNA as a template is believed to be packaged into preformed procapsids.
6. Cell lysis and virus release.