Impact of BHV-1 tegument proteins on the innate response to infection and virion morphogenesis.

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Bovine herpesvirus-1 (BoHV-1) has a severe impact on growth, milk production, and international livestock trade, thus being responsible for major economic damage to the cattle industry worldwide. In North America BoHV-1 is part of the bovine respiratory disease complex, which costs the cattle industry >1 billion dollars each year. In addition, BoHV-1 is an emerging virus in buffalo. Herpesviruses are composed of four concentric compartments, the nucleoprotein core, capsid, tegument and envelope. Tegument proteins are the first to interact with the intracellular environment and at a later stage associate to create the tegument of new virions. Some herpesvirus tegument proteins have important functions, for instance in regulation of transcription and in virus morphogenesis. The mechanism and site of BoHV-1 tegument formation, and the functions of its protein components are largely unknown.The overall goal of this program is to perform a functional characterization of the tegument proteins of BoHV-1. The short-term objective is to characterize the role of tegument protein VP8 in the host response to BoHV-1 infection, virus assembly and fitness. Infection of bovine cells or calves with BoHV-1 leads to a strong intrinsic host response. This suggests that the virus needs to counteract this response early during infection. VP8 is the most abundant viral protein, is detected in tissue culture at 2 h post-infection before de novo synthesis and is essential for infection of cattle. We hypothesize and already have evidence that VP8 plays an important role in overcoming early intrinsic defences of the host. We will further elucidate the mechanism and the critical domains of VP8 that are responsible for this phenomenon. Secondly, as the virion morphology and composition is altered in a VP8 deletion mutant virus, we hypothesize VP8 to play a role in virus morphogenesis. To investigate this, we will identify the VP8-protein interaction networks required for tegument formation and assembly of BoHV-1. The long-term objective is to characterize additional BoHV-1 tegument proteins. To obtain a basis for these studies, we will define the composition of BoHV-1 virions at different stages of maturation. This will lead to the identification of additional potentially important tegument proteins, to be further studied in context of BoHV-1 pathogenesis and morphogenesis.The results of this program are expected to have a significant impact on the rational design of attenuated BoHV-1 vaccines based on deletion or modification of specific virulence factors. Furthermore, therapeutics that target tegument proteins and interrupt initiation of infection or virus assembly may be developed. With the availability of cattle as the natural host for in vivo testing of new vaccines or therapeutics, which will expedite licensing, this work will quickly be of benefit to the livestock industry in Canada and worldwide.