Many lymphoproliferative disorders are known to result from viral infection including infection by human T lymphotropic virus (HTLV) and Epstein Barr virus. Bovine leukemia virus (BLV) is a retrovirus which causes a nonneoplastic B lymphocyte proliferation in infected cattle that may progress to lymphoma or leukemia and is closely related to HTLV both genetically and in the initiation of lymphocyte proliferation. The mechanism of proliferation has not been determined but is hypothesized to result from viral protein perturbation of normal proliferative pathways in the host cell. The goal of this project is to examine the role of the BLV transmembrane protein, gp30, on host cell activation. The BLV transmembrane protein, gp30, has sequence homology with the normal signal transducers of both B and T cells. In in vitro studies, chimeras of gp30 transduces activation signals from the cell surface, and mutation of the gp30 protein has been shown to decrease viral infectivity and proliferation in vivo. The proposed research will attempt to identify the role of gp30 in signal transmission and B cell activation. The hypothesis is that the BLV transmembrane protein gp30 initiates a tyrosine kinase signal pathway in infected host lymphocytes, leading to increased host cell activation.
Three specific aims will be used to test the hypothesis: i) identifying specific tyrosine kinases that interact with cytoplasmic gp30, ii) determine whether the levels of gp30 expression correlate to the presence and increased activation status of specific tyrosine kinases associated with gp30 and iii) determining if the identified tyrosine kinases activate infected lymphocytes. This research should provide insight into the mechanisms of normal signal pathways in B cells as well as methods by which viruses may subvert these mechanisms during infection. The candidate is a veterinarian completing a comparative pathology residency and is starting a Ph.D in comparative virology/immunology. The candidate has completed the didactic phase of the Ph.D. including preparation of an independent research proposal. The proposed project constitutes her doctoral research and will provide direction for the long-term goal of investigating mechanisms of viral/host interactions and cell regulation. Washington State University and the Department of Veterinary Microbiology and Pathology have a long history of successfully training graduate students. The faculty includes numerous successful researchers in the field of infectious diseases and students closely interact with the researchers.
| Hamilton, Valerie T; Stone, Diana M; Cantor, Glenn H (2003) Translocation of the B cell receptor to lipid rafts is inhibited in B cells from BLV-infected, persistent lymphocytosis cattle. Virology 315:135-47 |
| Hamilton, Valerie T; Stone, Diana M; Pritchard, Suzanne M et al. (2002) Bovine leukemia virus gp30 transmembrane (TM) protein is not tyrosine phosphorylated: examining potential interactions with host tyrosine-mediated signaling. Virus Res 90:155-69 |
