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Repeated emergence of epidemic/epizootic Venezuelan equine encephalitis from a single genotype of enzootic subtype ID virus.

ABSTRACT: Venezuelan equine encephalitis (VEE) epidemics and equine epizootics occurred periodically in the Americas from the 1920s until the early 1970s, when the causative viruses, subtypes IAB and IC, were postulated to have become extinct. Recent outbreaks in Columbia and Venezuela have renewed interest in the source of epidemic/epizootic viruses and their mechanism of interepizootic maintenance. We performed phylogenetic analyses of VEE virus isolates spanning the entire temporal and geographic range of strains available, using 857-nucleotide reverse transcription-PCR products including the E3 and E2 genes. Analyses indicated that epidemic/epizootic viruses are closely related to four distinct, enzootic subtype ID-like lineages. One of these lineages, which occurs in Columbia, Peru, and Venezuela, also included all of the epidemic/epizootic isolates; the remaining three ID-like lineages, which occur in Panama, Peru, Florida, coastal Ecuador, and southwestern Columbia, were apparently not associated with epizootic VEE emergence. Within the Columbia/Peru/Venezuela lineage, three distinct monophyletic groups of epidemic/epizootic viruses were delineated, indicating that VEE emergence has occurred independently at least three times (convergent evolution). Representative, complete E2 amino acid sequences were compared to identify potential determinants of equine virulence and epizootic emergence. Amino acids implicated previously in laboratory mouse attenuation generally did not vary among the natural isolates that we examined, indicating that they probably are not involved in equine virulence changes associated with VEE emergence. Most informative amino acids correlated with phylogenetic relationships rather than phenotypic characteristics, suggesting that VEE emergence has resulted from several distinct combinations of mutations that generate viruses with similar antigenic and equine virulence phenotypes.

SUBMITTER: Powers AM

PROVIDER: S-EPMC191949 | biostudies-other | 1997 Sep

REPOSITORIES: biostudies-other

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Repeated emergence of epidemic/epizootic Venezuelan equine encephalitis from a single genotype of enzootic subtype ID virus.

Powers A M AM Oberste M S MS Brault A C AC Rico-Hesse R R Schmura S M SM Smith J F JF Kang W W Sweeney W P WP Weaver S C SC

Journal of virology 19970901 9

Venezuelan equine encephalitis (VEE) epidemics and equine epizootics occurred periodically in the Americas from the 1920s until the early 1970s, when the causative viruses, subtypes IAB and IC, were postulated to have become extinct. Recent outbreaks in Columbia and Venezuela have renewed interest in the source of epidemic/epizootic viruses and their mechanism of interepizootic maintenance. We performed phylogenetic analyses of VEE virus isolates spanning the entire temporal and geographic range ...[more]

PMID: 9261393

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Project description:Venezuelan equine encephalitis virus (VEEV) is a New World Alphavirus that can cause neurological disease and death in humans and equines following transmission from infected mosquitoes. Despite the continued epidemic threat of VEEV, and its potential use as a bioterrorism agent, there are no FDA-approved antivirals or vaccines for treatment or prevention. Previously, we reported the discovery of a small molecule, ML336, with potent antiviral activity against VEEV. To further explore the population-level resistance profiles of ML336, we developed a whole-genome next-generation sequencing (NGS) approach to examine single nucleotide polymorphisms (SNPs) from virus passaged in dose escalation studies in a nonhuman primate kidney epithelial and a human astrocyte cell line, Vero 76 and SVGA, respectively. We passaged VEEV TC-83 in these two cell lines over seven concentrations of ML336, starting at 50 nM. NGS revealed several prominent mutations in the nonstructural protein (nsP) 3 and nsP4 genes that emerged consistently in these two distinct in vitro environments-notably, a mutation at Q210 in nsP4. Several of these mutations were stable following passaging in the absence of ML336 in Vero 76 cells. Network analyses showed that the trajectory of resistance differed between Vero and SVGA. Moreover, the penetration of SNPs was lower in SVGA. In conclusion, we show that the microenvironment influenced the SNP profile of VEEV TC-83. Understanding the dynamics of resistance in VEEV against newly developed antiviral compounds will guide the design of optimal drug candidates and dosing regimens for minimizing the emergence of resistant viruses.IMPORTANCE RNA viruses, including Venezuelan equine encephalitis virus (VEEV), have high mutation rates that allow for rapid adaptation to selective pressures in their environment. Antiviral compounds exert one such pressure on virus populations during infections. Next-generation sequencing allows for examination of viruses at the population level, which enables tracking of low levels of single-nucleotide polymorphisms in the population over time. Therefore, the timing and extent of the emergence of resistance to antivirals can be tracked and assessed. We show here that in VEEV, the trajectory and penetration of antiviral resistance reflected the microenvironment in which the virus population replicates. In summary, we show the diversity of VEEV within a single population under antiviral pressure and two distinct cell types, and we show that population dynamics in these viruses can be examined to better understand how they evolve over time.

Dataset Information

Repeated emergence of epidemic/epizootic Venezuelan equine encephalitis from a single genotype of enzootic subtype ID virus.

Publications

Repeated emergence of epidemic/epizootic Venezuelan equine encephalitis from a single genotype of enzootic subtype ID virus.

Similar Datasets

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