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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034479-08
Application #
3172209
Study Section
Virology Study Section (VR)
Project Start
1983-06-01
Project End
1991-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Wrzos, H; Gibbons, J; Abt, P L et al. (1990) Human herpesvirus 6 in monocytes of transplant patients. Lancet 335:486-7
Wrzos, H; Abt, P L; Rapp, F (1990) Anti-interferon antibody inhibits natural killer cell activity in HSV-2 genital infection in C57BL/6J mice. Intervirology 31:230-40
Nsiah, Y A; Tolman, R L; Karkas, J D et al. (1990) Suppression of herpes simplex virus type 1 reactivation from latency by (+-)-9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) in vitro. Antimicrob Agents Chemother 34:1551-5
Shiraki, K; Rapp, F (1989) Protein analysis of herpes simplex virus latency in vitro established with cycloheximide. Virology 172:346-9
Cockley, K D; Rapp, F (1989) Analysis of viral proteins in human cytomegalovirus-infected cells during impaired lytic replication of herpes simplex virus. Virology 170:268-72
Scheck, A C; Wigdahl, B; Rapp, F (1989) Transcriptional activity of the herpes simplex virus genome during establishment, maintenance, and reactivation of in vitro virus latency. Intervirology 30:121-36
Shiraki, K; Rapp, F (1988) Effects of caffeine on herpes simplex virus. Intervirology 29:235-40
Cockley, K D; Shiraki, K; Rapp, F (1988) A human cytomegalovirus function inhibits replication of herpes simplex virus. J Virol 62:188-95

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