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Envelope Glycoprotein Mutations Mediate Equine Amplification and Virulence of Epizootic Venezuelan Equine Encephalitis Virus

Ivorlyne P. Greene,^1,2 Slobodan Paessler,^1,2 Laura Austgen,³ Michael Anishchenko,^1,2 Aaron C. Brault,^1,2, Richard A. Bowen,³ and Scott C. Weaver^1,2*

Center for Biodefense and Emerging Infectious Diseases,¹ Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609,² Animal Reproduction and Biotechnology Lab, Colorado State University, Ft. Collins, Colorado 80522³

Received 14 February 2004/ Accepted 26 March 2005

Epidemics of Venezuelan equine encephalitis (VEE) result from high-titer equine viremia of IAB and IC subtype viruses that mediate increased mosquito transmission and spillover to humans. Previous genetic studies suggest that mutations in the E2 envelope glycoprotein allow relatively viremia-incompetent, enzootic subtype ID strains to adapt for equine replication, leading to VEE emergence. To test this hypothesis directly, chimeric VEEV strains containing the genetic backbone of enzootic subtype ID strains and the partial envelope glycoprotein genes of epizootic subtype IC and IAB strains, as well as reciprocal chimeras, were used for experimental infections of horses. Insertion of envelope genes from two different, closely related enzootic subtype ID strains into the epizootic backbones resulted in attenuation, demonstrating that the epizootic envelope genes are necessary for the equine-virulent and viremia-competent phenotypes. The partial epizootic envelope genes introduced into an enzootic ID backbone were sufficient to generate the virulent, viremia-competent equine phenotype. These results indicate that a small number of envelope gene mutations can generate an equine amplification-competent, epizootic VEEV from an enzootic progenitor and underscore the limitations of small animal models for evaluating and predicting the epizootic phenotype.

Present address: Center for Vector-borne Diseases and Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616.

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