CYTOMEGALOVIRUS AND HUMAN MALIGNANCY

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The overall objective of this project is to study the mechanism by which human cytomegalovirus (CMV) interacts with its host or with other infectious agents to result in malignant transformation of human cells. Efforts will be focused on the study of the co- etiological role of CMV in human malignancies. The hypothesis of this study is that the DNA of CMV morphological transforming region (mtr) alone is not sufficient to initiate the transformation of human cells. It may require transactivating factors provided from the expression of CMV immediate-early (IE) gene 1 and 2, transactivating gene. In addition, it is also hypothesized that CMV IE gene products are able to promote the transformation of human cells induced by other viral agents, such as human papilloma virus (HPV). Approaches include using recombinant DNA technology and other molecular biology techniques to investigate at molecular level the following specific aims: (1) To define the transactivating region of human CMV IE gene which is able to transactivate LTR promoter of human immunodeficiency virus and promoters of an early and a membrane antigens of Epstein-Barr virus. (2) To investigate whether transactivating CMV IE gene 1 and 2, and CMV mtr DNA (IE gene 4) can transactivate cellular ras oncogene expression which in turn leads to cell transformation, or vice versa. (3) To investigate whether CMV IE gene can promote the transforming efficiencies of CMV mtr DNA fragment (HindIII A-BamH1J), or HPV type 16 and 18 DNA s in human fibroblasts and cervical epithelial cells. (4) To examine whether infectious CMV or CMV IE gene 1 and 2 can transactivate the expression and replication of HPV 16 and type 18 in human cells. (5) To establish a pilot study to detect CMV DNA and HPV DNA sequences, viral mRNA's and oncogenes expression in cervical cancers for studying there possible etiological role in cervical cancer. (6) To detect CMV related DNA and mRNA sequences, and cellular oncogene expression in Kaposi's sarcoma, and to analyze the statistical significance of these data.