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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report
documented in poliovirus replication (Crotty et al. 2000; de la Torre et al. 1990). Quasi-species present a dynamic equilibrium of many viral geno-types in which the identity of the wild type is maintained only because of strong selection against a continuously appearing spectrum of mutants. As has been apparent in the development of drugs against many RNA viruses, the existence of a pool of variants makes it likely that mutants resistant to a given drug (“escape” mutants) already exist in the population before the drug is even used (Coffin 1995).
The speed with which drug resistance will emerge is difficult to predict since it depends on the target chosen for inhibition and the circumstances in which the drug would be used. However, an ideal polio antiviral drug will have features that slow the emergence of resistant mutants. One way to minimize or avoid the rapid emergence of escape mutants is to design a drug so that resistant viral variants are much less fit than nonresistant viruses. For example, oseltamivir, a drug that inhibits influenza neuraminidase, binds to a highly conserved active site, so variants resistant to the inhibitor also have greatly reduced neuraminidase activity and replicate poorly (Carr et al. 2002). An even more sophisticated strategy is to design the drug so that resistant mutants actually interfere with nonresistant viruses. Resistant mutants with this characteristic are said to have a “dominant negative” effect. For example, a mutation resulting in a misfolded protein that binds to and interferes with the function of normally folded proteins would be likely to have such a dominant negative effect (Crowder and Kirkegaard 2005).
SYNOPSIS OF POLIOVIRUS PATHOGENESIS AND REPLICATION
Poliovirus is a highly contagious virus that belongs to the genus Enterovirus of the large family of Picornaviridae (Stanway et al. 2002). Picornaviruses have been estimated to cause an astounding 6 billion human infections per year, and they give rise to a wide array of serious, even lethal, diseases (Melnick 1996). Enteroviruses alone (about 100 serotypes) are responsible for 1 billion infections per year. Enterovirus infections, including those caused by poliovirus, are largely covert, but the vast incidence of infections translates into a large number of clinical cases.
This report is not intended as an exhaustive review of all steps in cellular poliovirus replication or pathogenesis. Some details of the interaction of the virion (an individual virus particle) with the receptor CD155, of polyprotein synthesis and processing, and genome replication will be pro-