Viruses From Structure to Biology

Both rhinoviruses and poliovirus are human pathogens. We have probably all been infected by rhinoviruses but as unpleasant as a cold can be, these "cold viruses" never generated the fear that poliovirus once did. It was only with the development of very effective vaccines against poliovirus that this virus was transformed from a terror to a tool for molecular biologists. Today, poliovirus is recognized as one of the most important models for understanding the replication of animal RNA viruses. The development of vaccines also made the goal of eradication of the disease of poliomyelitis a reality.

In 1985, Jim Hogle and his collaborators solved the structure of poliovirus to a resolution of 2.9 angstroms (Hogle, Chow and Filman, Science 229: 1358-1365). One factor in achieving this goal had been that, because of the vaccines, it was possible to work with the virulent Mahoney strain which gave more stable crystals than the attenuated (Sabin) strain.

What did we learn from the structure? When Jim was in Steve Harrison's lab he had solved the structure of, turnip crinkle virus, a virus very similar to tomato bushy stunt virus and was very much aware that the protein of plant RNA virus structures had long arms that would be disordered except when they became part of a more complex structure. In Jim's words:

"Well, there were several things that were really stunning in the structure that we tried to talk about in the paper. One was that the theme of interlocking of N-terminal arms of subunits, that had been seen before in TBSV, was expanded on in a gorgeous way in the structure. The entire inner surface of the capsid is decorated by an elaborate interaction of N-terminal extensions of VP1, 2 and 3 and by VP4."

It had been known since 1968 that the poliovirus genome contains a single large open reading frame and that the individual proteins of the virus particle (VP1, 2, 3 and 4) are produced by proteolytic cleavages from a larger precursor. In the structure, the amino- and carboxy-termini generated by proteolysis are spatially distinct. Jim described this in more detail and concluded:

"It was clear that the interfaces that existed in the virus itself couldn't exist in the same form until after cleavage. That was great because it said that proteolysis is not just a convenient way to make a lot of proteins from one gene, it is also a great way to control the timing of assembly."

Jim also noted, both in the Science paper and in our conversation, that there are extensive similarities between the structure of poliovirus and the previously solved plant viruses, but said that poliovirus was decorated with more elaborate loops and these elaborate loops were the site of the monoclonal antibody escape mutations. Many of the antigenic sites on poliovirus had been identified by using synthetic peptides that induced neutralizing antibodies. Most of these antigenic sites mapped to the outer surface of the virion particle - as expected. But there were exceptions. Some peptides able to induce neutralizing antibodies were buried deep in the interior of the virion. At the time the authors commented: "The ability of these buried peptides to induce an antiviral response may prove to be important in understanding the mechanism of neutralization". Although not discussed at the time, they must have also been thinking about disassembly of the particle. Their subsequent studies have demonstrated that this kind of conformational flexibility must play a significant role in the uncoating of the virus that would accompany cell entry (Li, Q, Gomez, Y., Lee, Y.M.-H, Hogle, J. and Chow, M. 1994 J. Virol. 68: 3965-3970).

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| Introduction | Some historical highlights: structural virology and virology |
| Solving the Structure of Icosahedral Plant Viruses | Picornavirus Structure | Poliovirus | Polio
The Influenza Virus Hemagglutinin
| The Influenza Virus Neuraminidase |
Issues of Science and Society |contributors|
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