The Polyomaviridae: Contributions of virus structure to our understanding of virus receptors and infectious entry

Abstract

This review summarizes the field's major findings related to the characterization of polyomavirus structures and to the characterization of virus receptors and mechanisms of host cell invasion. The four members of the family that have received the most attention in this regard are the mouse polyomavirus (mPyV), the monkey polyomavirus SV40, and the two human polyomaviruses, JCV and BKV. The structures of both the mPyV and SV40 alone and in complex with receptor fragments have been solved to high resolution. The majority of polyomaviruses recognize terminal sialic acid in either an alpha2,3 linkage or an alpha2,6 linkage to the underlying galactose. Studies on virus structure, receptor utilization and mechanisms of entry have led to new insights into how these viruses interact in an active way with cells to ensure the nuclear delivery and expression of their genomes. Critical work on virus entry has led to the discovery of a pH neutral endocytic compartment that accepts cargo from caveolae and to novel roles for endoplasmic reticulum (ER) associated factors in virus uncoating and penetration of ER membranes. This review will summarize the major findings and compare and contrast the mechanisms used by these viruses to infect cells.

Fig. 1

Early model of polyomavirus attachment, penetration, and nuclear entry. Open virions represent empty capsids that are found to be internalized in large endosomal vesicles that presumably lead to degradation. Closed virions represent infectious particles and unlike empty capsids these are internalized into monopinocytotic vesicles. Some virions were found in large tubular structures that likely represent the pinching off of these structures from caveosomes described years later by Helenius (see text for detailed descriptions). Modified from information in Mackay and Consigli, 1976 and Maul et al., 1978.

Fig. 2

General model of infectious entry pathways utilized by polyomaviruses. JCV is unique in that it initially enters cells by clathrin dependent endocytosis. The virus then traffics to early endosomes and then to caveosomes. BKV, SV40, and mPyV are reported to use caveolae dependent mechanisms of entry that traffic these viruses to caveosomes. SV40 and mPyV can also use non-caveolar but cholesterol dependent mechanisms of entry to access the caveosome and the mechanism used depends on cell type. Once in the caveosome SV40 and mPyV traffic to the endoplasmic reticulum in tubular structures that bud off the ER membrane. It is presumed that JCV and BKV use the same pathway but data on this is lacking. Adapted from Marsh and Helenius, 1989.

Fig. 3

Mechanisms used by polyomaviruses to exit the ER and target their genomes to the nucleus. The mouse polyomavirus and SV40 both traffic to the ER and it is presumed but not formally proven that JCV and BKV do the same. Once in the ER mPyV utilizes the unusual PDI family member, ERp29 to induce a conformational change in its coat protein. This may lead to cleavage of the C-terminal arm of VP1 allowing the particle to bind to lipid membranes. The ER retrotranslocation protein Derlin 2 is involved in ER exit. SV40 utilizes the canonical ER oxidoreductases, PDI, and ERp57, to unravel 12 of the vertex pentamers in the virus shell. This unfolded protein is then recognized by components of the ER associated degradation (ERAD) pathway (Derlin 1 and SelL1) to exit the ER. The viruses encounter a low calcium environment in the cytosol that may allow for their further disassembly. Once disassembled the viral protein–mini-chromosome complex is transported across an intact nuclear pore for genome delivery to the nucleus.

Fig. 4

Sialic acid recognition by viral attachment proteins. (A) Schematic of N-acetyl neuraminic acid. The arrow points to the O2 oxygen that is involved in glycosidic linkages to adjacent sugars. (B–F) Contacts of NeuNAc with Influenza HA (B), Ad37 (C), Rotavirus VP8⁎ (D), mPyV VP1 (E) and SV40 VP1 (F). pdb entries 1hgg (B), 1uxa (C), 1kqr (A, D), 1vps (E) and 1bwr (F) were used to create this figure. NeuNAc is depicted in orange, the protein residues forming hydrogen bonds to NeuNAc are colored green and the residues making van der Waals contacts are colored grey. The viral surface is shown in grey. This figure was prepared with PyMol (DeLano Scientific, Inc.).