Epstein-Barr virus (EBV) is a human herpesvirus which is a prime candidate for a human cancer virus. EBV is strongly associated with two malignancies, nasopharyngeal carcinoma and Burkitt's lymphoma, induces fatal lymphoma following injection into nonhuman primates, and transforms B lymphocytes in vitro, thereby generating permanent cell lines. In economically developed countries, it causes infectious mononucleosis, a benign lymphoproliferative disease which may progress to fatal lymphoproliferative malignancy in immunologically compromised individuals with Duncan's disease or in allograft recipients. Recent studies have also implicated EBV as a potential factor in the development of several autoimmune diseases. Over 90% of adults carry the viral genome for life in latent form in B lymphocytes and in oropharyngeal cells. The immune system is involved in the maintenance of the latent state. Despite the importance of EBV in human disease, relatively little is known of the early events in infection of cells by the virus. It is the objective of this program to investigate the basic mechanisms by which this virus recognizes, enters and progresses to its nuclear site of replication within the normal human B lymphocyte. Identification and characterization of the EBV receptor as well as the tropism of EBV in binding to B cell and T cell subpopulations will be analyzed. The roles of the major viral envelope proteins and cellular elements in viral attachment/deenvelopment and fusion are to be studied. Our recent studies showed that EBV enters B cells by endocytosis into large, thin-walled endocytic vacuoles where deenvelopment/fusion and entry of the nucleocapsid into the cytoplasm occurs by a pH dependent event not involving lysosomal enzymes. The nature of the pH requirement and its source will be further analyzed. Since our preliminary studies suggest that actin microfilaments participate in EBV deenvelopment in B cells the role of the cell cytoskeleton, particularly actin and myosin in viral attachment, entry and deenvelopment are also to be analyzed. The overall approach to this project will be biochemical and molecular in naturel utilizing modern techniques, purified cells, proteins and specific probes wherever possible to study EBV cellular interactions. Analysis of cell-virus interactions will also be correlated with functional relevance as indicated by infectivity and cell transformation. The ultimate goal of these studies is the understanding on a molecular level of the means by which this virus initiates infection.
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