SV40 Pathogenesis of Human Infections

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DESCRIPTION (provided by applicant): Persuasive evidence now indicates that SV40 is causing infections in the human population today. The Institute of Medicine recently concluded "the biological evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions" and recommended "further study of the transmissibility of SV40 in humans". Specific human tumor types associated with SV40 include non-Hodgkin's lymphoma. The goals of this proposal are to evaluate the pathogenesis and transmissibility of SV40 in humans and to determine if the variable domain at the carboxy (C) terminus of the viral large T-antigen (T-ag), is functionally important in viral pathogenesis. The specific aims are the following: (1) Determine the prevalence, transmission, and morbidity of SV40 infections in a target human population (organ transplant recipients). We will evaluate prospectively the presence of SV40 in peripheral blood cells and in urine among adult transplant patients. SV40 strains will be characterized and the state and expression of the viral genome in human tissues and malignancies determined. Clinical and pathological correlations will be established between SV40 infections and disease, including the development of systemic lymphomas. (2) Determine the influence of SV40 strain variation on viral replication in human peripheral blood mononuclear cells (PBMCs) and on immortalization of B-cell lymphocytes. Different SV40 strains will be tested for replication potential in subsets of PBMCs and for immortalization ability in B lymphocytes. The state and expression of viral DNA in immortalized B-cells will be determined. Viral regulatory region changes will be monitored in infected PBMCs. (3) Identify C-terminal T-ag interactive cellular proteins. An SV40 T-ag derived from human malignancies will be used to screen a human lymphocyte cDNA library using the yeast two-hybrid system; interactive protein(s) that recognize the C-terminal domain of T-ag will be characterized; interactions with wild-type and mutant T-ags will be compared. This program addresses important gaps in our knowledge concerning the transmission and pathogenesis of SV40 infections in humans. It will reveal if SV40 strains vary in pathogenic effects in humans and the possible role of the C-terminal T-ag domain in those processes. This new information will allow better understanding of the biology of SV40 human infections and may provide insights into the mechanisms of SV40 involvement in human malignancies.