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The Molecular Perspective: Simian Virus 40

David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu WorldWideWeb:http://www.scripps.edu/pub/goodsell

Simian virus 40 (SV40) is an exercise in biological parsimony. With a minimum of molecular machinery, this DNA tumor virus enters a cell, reproduces itself, and escapes. In most cases, this has little consequence for the infected animal: SV40 does not cause disease in the wild. But in rare cases, or under the unusual conditions studied in the laboratory, SV40 can transform cells into a cancerous state. This is not a mere curiosity, however, as roughly 15% of human cancers appear to involve similar virus infections.

SV40 is composed of a small circle of DNA, enclosed in a simple protein capsid. As shown in Figure 1, the genome encodes only a handful of proteins: two T-antigens, three capsid proteins, and a small "agnoprotein" of unknown function. Together, these orchestrate a remarkably economical lifecycle.

View larger version (41K): [in this window] [in a new window]   Figure 1. The genome of SV40. The entire viral genome is a circle of double-stranded DNA 5243 base pairs in length, shown here flattened out on the page. In the cell and in the capsid, this DNA is wound around nucleosomes to form a "mini-chromosome." The regulatory region is shown at the right. The long region in yellow is the origin of replication and the various sequences involved in transcriptional regulation are in red and orange. Two regions encode protein on the circle. The "early" region is at the top, encoding the large T-antigen in two pieces (the mRNA is spliced in the cell to remove the intron) and the small T-antigen. The "late" region is at the bottom of the circle, encoding three capsid proteins and a small "agnoprotein" of unknown function. For economy, the genes for the capsid proteins VP1, VP2, and VP3 overlap extensively: VP3 is a truncated version of VP2 and the region encoding VP2 and VP3 overlaps the region encoding VP1, but in an alternate reading frame. Only the small white stretches of DNA do not have direct coding or regulatory functions. The capsid is shown here at the center for comparison of size. Only the VP1 shell is shown—VP2 and VP3 are thought to bind at the center of each of the bumps, extending outward from the capsid. The genome of SV40 was accessed at the National Center for Biotechnology Information; Bethesca, MD (http://www.ncbi.nlm.nih.gov) and atomic coordinates for the capsid were taken from the entry 1sva at the Protein Data Bank (http://www.rcsb.org/pdb).

The genome contains a regulatory region packed with instructions. At its center is a TATA sequence similar to the ones used by our cells to initiate transcription. Boosted by three GC-rich promotors and two large enhancers, this TATA sequence directs the formation of an "early" transcript of the genome, copied in a counterclockwise direction in the figure and extending about halfway around the circle. This transcription is performed by the cell's own machinery. Unbeknownst to the cell, by transcribing this mRNA the cell relinquishes control to the virus.

The mRNA is translated primarily into a single protein, the large T-antigen (a smaller protein, the small T-antigen, is also formed. Its function is not well understood). The T-antigen then reenters the nucleus, using a nuclear location signal as passport. It then does everything. It binds to the tumor suppressor proteins Rb and p53, overriding the normal controls on growth and kicking the cell into full DNA-replication mode. Twelve molecules of T-antigen bind to the origin of replication on the SV40 DNA circle, prying the two strands apart and making them ready for replication. The T-antigen also binds to intact double-stranded circles and directs the transcription of a second mRNA, this time extending in the clockwise direction halfway around the circle. This mRNA then directs the synthesis of capsid proteins in the cytoplasm. Finally, all of these new capsid proteins assemble into virions, each capturing a nucleosome-decorated circle of DNA.

This is the normal lifecycle of the virus. But in rare cases, when the virus infects a "nonpermissive" cell, viral replication is inhibited. In even rarer cases, the virus may integrate into the genome of these cells, with dire consequences. If the virus integrates into a region that is actively transcribed, the cell will then produce quantities of T-antigen, as the integrated SV40 genome is transcribed along with the normal cellular genes. This T-antigen will have the same effect as in permissive cells—it will migrate to the nucleus, bind to Rb and p53. But in this case, the cell will not produce new viruses. Instead, the cell will be transformed, losing its normal controls on growth. This is a rare event in SV40, but it is more common in the related papillomaviruses, where integration and expression of viral proteins can lead to benign proliferation to form warts or more malignant transformations.

ADDITIONAL READING

• Cole CN. Polyomavirinae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM, et al., eds. Fields Virology, Third Edition. Philadelphia: Lippincott-Raven, 1996:1997-2025.
  
• Liddington RC, Yan Y, Moulai J et al. Structure of simian virus 40 at 3.8-A resolution. Nature 1991;354:278-284.
  
• Zur Hausen H. Viruses in human cancers. Science 1991;254:1167-1173.
  

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