Research - The Epstein-Barr Virus (EBV) is the cause of acute infectious mononucleosis. Malignant cells from African Burkitt's lymphoma and nasopharyngeal carcinoma contain EBV genomes as do lymphocytes from the polyclonal B cell lymphomas currently seen in transplant recipients and among patients with AIDS. The EBVR is a approximately 140,000 Mr cell surface glycoprotein that is identical to the receptor for the cleavage fragment of the third component of complement, C3d (CR2). The receptor is normally expressed on mature human B lymphocytes, but is absent on pre-B cells and plasma cells. Expression of the EBVR/CR2 has also been described on follicular dendritic cells, oropharyngeal epithelial cells, Histiocytosis X cells, platelets and rare T-lymphoblastoid cell lines. A functional role in early B cell activation has been postulated. The density of EBVR/CR2 on circulating B lymphocytes is decreased in diseases associated with polyclonal B cell activation such as systemic lupus erythematosus and AIDS. It is anticipated that recombinant bacterial synthesis of the virion envelope glycoprotein(s) gp350/220 which mediate attachment to the receptor will form the basis of a future anti-tumor vaccine. Therefore, it is extremely important to characterize the nature of the interaction between the viral glycoproteins and the receptor in order to maximize vaccine efficacy and prevent unanticipated adverse effects which could result from creating autoantibodies to the natural ligand C3d, or from inadvertantly triggering the receptor molecule. During the first two years of this proposal the EBVR/CR2 was biochemically characterized. The molecule was purified and the amino acid sequence of the N-terminus as well as internal tryptic fragments was determined. The receptor was described on T-lymphoblastoid cell lines having a thymic phenotype and the putative murine CR2 was identified. Oligonucleotide probes derived from protein sequence were used to clone the receptor. During the next 2-3 years of this proposal, the cloned receptor will be expressed and mutagenized in order to fully characterize the nature of virus/receptor, C3d/receptor and membrane/receptor interactions. Additional functional studies will performed to more clearly define the role of the EBVR/CR2 in B-cell activation/differentiation. The putative murine CR2 will be cloned and characterized. The murine receptor, which is not an EBV receptor, will be compared with the human receptor in order to elucidate the structural requirements for virus binding. Receptor function in inbred immunodeficient mice will be examined. Candidate - The applicant's long term objective is to continue to do research and practice clinical infectious diseases in an academic setting. She completed a three-year Infectious Disease Fellowship at the Beth Israel Hospital, Boston, Mass. in July, 1983. From 1983-1985, she was a full-time post-doctoral Research Fellow in the laboratory of Dr. Jack Strominger in the Division of Tumor Virology at the Dana-Farber Cancer Institute and had an appointment as an Instructor of Medicine at the Harvard Medical School. In 1985, she received a three year Clinical Investigator Award, and the following year became a full-time member of the Department of Infectious Diseases at the Dana-Farber Cancer Institute. Her primary research interest is on the nature of the EBVR/CR2 its role in viral infection and immune responsiveness. Environment - The sponsor's laboratory is expert in viral immunology and mechanisms of host-viral interaction.
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