Genetic and phenotypic changes accompanying the emergence of epizootic subtype IC Venezuelan equine encephalitis viruses from an enzootic subtype ID progenitor

Recent studies have indicated that epizootic Venezuelan equine encephalitis (VEE) viruses can evolve fi om enzootic subtype ID strains that circulate continuously in lowland tropical forests (A. M. Powers, M. S. Oberste. A. C . Brault, R. Rico-Hesse, S. M. Schmura, J. F. Smith, W. Kang, W. P, Sweeney , and S. C, Weaver, J. Virol, 71:6697-6705, 1997), To identify mutations as sociated with the phenotypic changes leading to epizootics, we sequenced th e entire genomes of two subtype IC epizootic VEE virus strains isolated dur ing a 1992-1993 Venezuelan outbreak and four sympatric, subtype ID enzootic strains closely related to the predicted epizootic progenitor. Analysis by maximum-parsimony phylogenetic methods revealed 25 nucleotide differences which were predicted to have accompanied the 1992 epizootic emergence; 7 of these encoded amino acid changes in the nsP1, nsP3, capsid, and E2 envelop e glycoprotein, and 2 were mutations in the 3' untranslated genome region. Comparisons with the genomic sequences of IAB and other IC epizootic VEE vi rus strains revealed that only one of the seven amino acid changes associat ed with the 1992 emergence, a threonine-to-methionine change at position 36 0 of the nsP3 protein, accompanied another VEE virus emergence event. Two c hanges in the E2 envelope glycoprotein region believed to include the major antigenic determinants, both involving replacement of uncharged residues w ith arginine, are also candidates for epizootic determinants.