The overall goal of these studies is to understand at the molecular level the pathogenesis of herpes simplex virus type 2 (HSV-2) infection: particularly with regard to the way HSV-2 may contribute to the progression of human malignancies, and to the mechansim by which HSV can initiate, maintain and be reactivated from latent infections. As a model system, the ability of HSV-2 to morphologically transform cells in culture will be studied. Previous studies have localized the morphological transforming region (mtr) to 792bp segment within the Bg1II N fragment. Studies are proposed to precisely define the active sequences and to determine whether an IS-like element is involved. Studies to address the mechanism of transformation focus on establishing whether the event is truly """"""""hit-and-run"""""""", whether gene rearrangements occur, whether cellular sequences are transposed, and evaluating the mutagenic capacity of the mtr. Other transformation assayas will be used to identify potential new mtrs. One current hypothesis about the etiology of cervical cancer is that HSV and HPV may act synergistically to contribute to alterations in a cell. A series of experiments are outlined to ellucidate the mechanism by which HSV infection can amplify resident HPV sequences in cervical carcinoma cells. Additionally, the ability of HSV to induce replication or transcription of the HPV genome will be investigated. Finally, studies are proposed to re-examine human sensory ganglia for HSV transcripts by in situ hybridization using single stranded RNA grobes for specific HSV IE genes. The ability of selected HSV and CMV promoters to respond to glucocorticoids, hormones, etc will be examined as a basis to understand reactivation.
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