Inhibition of Type-1 Interferon Response by EHV-1

Equine herpesvirus-1 (EHV1) is a major pathogen of horses whose control has been elusive. Like other herpesviruses, EHV1 appears to have multiple mechanisms for evading host immune responses. Least studied of these has been evasion of the Type-1 interferon response (IFN-á/â). IFN-á/â is important to innate immune responses by inducing a non-specific antiviral state, and now it is recognized as important for strong adaptive (humoral/CTL) immune responses to some viruses. Our hypothesis is that EHV1 virus-coded factors function to suppress the host IFN-á/â response in infected cells, and this is part of the mechanism of EHV1 pathogenesis. Our preliminary data show that after an initial stimulation, EHV1 infection suppresses cellular IFN-á/â probably by activity of a late-expressed viral protein. Specific objectives include: 1). To determine the point(s) in the molecular pathways of IFN-á/â sensitization/-induction/amplification that are specifically attacked by EHV1-mediated suppression. 2) To compare differential pathogenicity of EHV1 strains with their ability to suppress the IFN-á/â response. Expected outcomes include identification of the molecular mechanism by which EHV1 suppresses IFN-á/â, and understanding of how this contributes to EHV1 pathogenesis. Potential impacts include the possibility that with this understanding, we can take advantage of recent advances such as the complete gene sequence of the horse, to design interventions to circumvent IFN-á/â suppression and bolster innate or adaptive immune responses against EHV1, leading to improved control of this disease.