Immune recognition and function of Bovine Viral Diarrhea Virus envelope proteins

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Bovine Viral Diarrhea Virus (BVDV) is highly prevalent among cattle herds in Canada. This circulation of BVDV continues to cause significant economic losses in both dairy and beef herds. In infected pregnant cows, the fetus contracts the virus transplacentally during the first trimester of gestation. This calf will become persistently infected (PI), and will not mount an immune response against this virus. The resulting calf is BVDV immunotolerant at birth and will shed large quantities of BVDV throughout its life. These PI animals are considered the main source of new BVDV infections and continued virus circulation. To better understand how these viruses evolve and persist in their host it is essential to study the virus natural antigenic variability. These antigenic changes exhibited by the virus over time are determined by the way hosts and pathogens interact. We have used these PIs to study virus inter- and intra-host variability which will be used to establish evolutionary models that can infer BVDV evolution. The high mutation rate of BVDV is posing challenges for both the host immune response and the researcher that aims to develop vaccines to prevent infections with these pathogens. This component of the program specifically aims to elucidate the properties of the two most antigenic envelope proteins of BVDV. In this study we will explore two different ways to quantify the antigen-antibody interaction. A series of different monoclonal and polyclonal antibodies and several naturally occurring BVDV variants will be examined (Objective I). We will better understand the determinants of antibody binding to a specific antigen and we can compare the antigenicity of the various strains. To more precisely identify the parts of the BVDV envelope proteins that are recognized by the immune system, we will map the amino-acids that are involved in immune recognition using two different, but complementary strategies (Objective II). This will provide us with an overview of the parts that are recognized by the immune system and are likely to undergo evolutionary change in the future. The last component of this proposal (Objective III) will study the sugar-structures (N-glycosylation) of these envelope glycoproteins. These sugars have very important roles in the virus lifecycle and can influence the way the immune system of the host will recognize the virus. N-glycosylation can play a significant role in immune-escape. By posing specific selective pressures on these sugar structures we force the virus to adapt. This will reveal the options for the virus to modify these crucial components of the glycoprotein. The current studies are expected to provide novel insights in the way BVDV interacts with its bovine host and will generate new information on virus variability and evolution. All this information will lead to a new way to infer virus evolution and how we construct BVDV vaccines.