The interaction of herpes simplex virus (HSV) with its human host may result in infectious disease, virus persistence or latency, or possible neoplasia. The outcome of this host-pathogen interaction in humans or experimental systems is determined, in part, by the nature of the host cell types involved in conjunction with immunological, physiological, and other modulating factors. The understanding of these interrelated pathological processes has been greatly facilitated by the complementary use of both in vitro and in vivo models. It has been generally acknowledged that during HSV infection of humans and experimental animals virus latency is established in the peripheral nervous system, with virus reactivation resulting in virus shedding or recurrent disease that may be life-threatening in the immunocompromised cancer patient and may be a factor or cofactor in the causation of human neoplasia. The central objective of the prosposed research is to exploit a series of in vitro virus latency systems employing human sensory neurons and fibroblasts as host cells to examine (i) the mechanisms of establishment and maintenance of HSV latency; (ii) the state of the latent HSV genome; (iii) the mechanism of virus reactivation; (iv) the effect of virus latency on neuronal function; (v) the effect of a latent HSV genome on human cell transformation; (vi) the effect of human cell transformation on establishment and maintenance of virus latency, and (vii) the effect of therapeutic agents on virus latency, reactivation, and cell transformation. Scientific disciplines involved will include oncology, neurology, molecular biology, neurobiology, and genetics with the experimental application of human nerve cell culture, DNA- and RNA-specific dot, blot, and in situ hybridization procedures, protein analysis with virus- and neuron-specific monoclonal antibody probes, hybridoma technology, and fluorescence-activated flow cytometry. These studies are health-related because they deal with ubiquitous viruses [HSV and human cytomegalovirus (HCMV)] that can cause latent and chronic infections and overt life-threatening clinical disease in their human host. Furthermore, HSV and HCMV have been associated with human neoplasia; cervical carcinoma and Kaposi sarcoma, respectively. The project results should enable better understanding of how herpesviruses cause latent and chronic infections and cancer and may ultimately, provide means for early diagnosis, cure, or prevention of the many diseases caused by these viruses.
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