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Structural and Nonstructural Protein Genome Regions of Eastern Equine Encephalitis Virus Are Determinants of Interferon Sensitivity and Murine Virulence

Patricia V. Aguilar,^1,2, A. Paige Adams,^1,3, Eryu Wang,^1,3 Wenli Kang,^1,3 Anne-Sophie Carrara,^1,3 Michael Anishchenko,^1,3 Ilya Frolov,^1,2 and Scott C. Weaver^1,2,3*

Center for Biodefense and Emerging Infectious Diseases,¹ Department of Microbiology and Immunology,² Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609³

Received 24 November 2007/ Accepted 22 February 2008

Eastern equine encephalitis virus (EEEV) causes sporadic epidemics of human and equine disease in North America, but South American strains have seldom been associated with human neurologic disease or mortality, despite serological evidence of infection. In mice, most North American and South American strains of EEEV produce neurologic disease that resembles that associated with human and equine infections. We identified a South American strain that is unable to replicate efficiently in the brain or cause fatal disease in mice yet produces 10-fold higher viremia than virulent EEEV strains. The avirulent South American strain was also sensitive to human interferon (IFN)-, -β, and -, like most South American strains, in contrast to North American strains that were highly resistant. To identify genes associated with IFN sensitivity and virulence, infectious cDNA clones of a virulent North American strain and the avirulent South American strain were constructed. Two reciprocal chimeric viruses containing swapped structural and nonstructural protein gene regions of the North American and South American strains were also constructed and found to replicate efficiently in vitro. Both chimeras produced fatal disease in mice, similar to that caused by the virulent North American strain. Both chimeric viruses also exhibited intermediate sensitivity to human IFN-, -β, and - compared to that of the North American and South American strains. Virulence 50% lethal dose assays and serial sacrifice experiments further demonstrated that both structural and nonstructural proteins are important contributors to neurovirulence and viral tissue tropism. Together, the results of this study emphasize the complex and important influences of structural and nonstructural protein gene regions on EEEV virulence.

Published ahead of print on 19 March 2008.

These authors contributed equally to this work.