Genome Variability

In the rabies virus life cycle, the genome RNA is subject to limited replication fidelity due to an absence of RNA proofreading/repair and postreplication error-correction mechanisms. Consequently, mutations that are introduced at a relatively high frequency, by the "error-prone" virion-associated RNA polymerase as the enzyme replicates the genome RNA, remain in the genome RNA. This produces a population of different viral genomes that share a common origin; i.e., they are related but distinct (Kissi et al., 1999). Genome RNA mutations (misincorporation of nucleotides) occur at different rates, on the order of 10~4 to 10~5 substitutions per nucleotide per cycle, depending on the region of the genome RNA considered (Domingo and Holland, 1997; Bracho et al., 1998; Kissi et al., 1999). On the one hand, the genetic variation in complex mixtures of related genomes has resulted in such major comprehensive differences that viruses could be sorted taxonomi-cally into different families, genera, and species. In other cases of less marked differences, genetic variations have provided the basis for grouping viruses into serotypes, genotypes, or phenotypes within a genus or virus species. Several other factors that may be involved in generating RNA sequence heterogeneity in rabies virus include duration of infection, route of transmission, virus load, host immune response, and virus-host protein cooperation (Kissi et al., 1999). Despite these other influences, the infidelity of the RNA polymerase of negative-strand RNA viruses remains the single major factor responsible for the nucleotide misincorporation in the genome RNA. Assuming a random distribution of mutations among the population of replicating genomes, the variant genomes form complex "quasi-species" populations that increase very rapidly within infection cycles over time (reviewed in Holland et al., 1992; Smith et al., 1997; Domingo and Holland, 1997). As a result of this extreme form of genetic instability, out of a quasi-species population of rabies viral RNA genomes, a true rabies virus variant may evolve that harbors a specific mutation or set of specific mutations capable of imparting to the virus a distinctive phenotypic or unique virus-host relationship. For example, several mutations have been identified in protein coding regions of the genome of virus variants that correlate with a selective tropism for neurons or for an avirulent phenotype of the virus in a particular animal host (Murphy and Nathanson, 1984; Domingo et al., 1998; Morimoto et al., 1998). Mutations in noncoding regions of the genome also may affect the balance between replication of standard versus defective genomes and possibly increasing or decreasing survival of the infected cell or animal host. Or they may influence long-term survival (persistence) of the virus in its host as a result of specific interactions between viral and host determinants (Domingo et al., 1998). The quasi-species model of mixed RNA virus populations provides a plausible explanation for the rapid selection of mutants that fit into any new environmental condition (Morimoto et al., 1998). This selection process may occur in any of the viral genes whose proteins influence the particular structure, function, or phenotype of the virus.

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