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Nigel
W. Fraser, Ph.D.
Professor, Dept of Microbiology
319 Johnson Pavilion
3610 Hamilton Walk
(215) 898-3847 FAX: (215) 898-3849
email: nfraser@mail.med.upenn.edu
Click here for selected publications since Dr. Fraser's arrival at Penn
RESEARCH INTERESTS
Herpes Simplex Virus latency; Viral Gene and Cancer therapy RESEARCH TECHNIQUES
Molecular biology - cloning, sequencing, expression vectors, Northern, Southern, and Northwestern blots, gel shifts, differential display; Virology - mouse eye model for latent viral infections, intercranial tumor models for brain therapy, viral titering, mutant production, etc.RESEARCH SUMMARY
My group has shown that the physical state of the latent viral DNA is episomal and not integrated, and that it is harbored in the trigeminal ganglia and brain stem of latently infected mice. Using in situ hybridization, we have shown that there is transcription during latency and that transcripts are restricted to a small region of the viral genome - the repeat long region. Using Northern blot analysis, we are mapping latent transcripts within this region of the genome. Recently we have genetically engineered deletion mutants of HSV-1 that do not express any RNA during latency. The results of these experiments suggest that the role of the genes expressed during latency is in the reactivation stage of the infection. A virion protein Vp16 has been shown to play an important role in transactivating the viral immediate early genes. We have used a virus which is defective in the transactivating function of Vp16 to show that this gene is essential for replication in the nervous system and that a cellular factor present in tissue culture cells can complement this function. Work is continuing to define cellular transcription factors from neuronal cells and nervous system tissue which modulate HSV gene expression. Our long-range goal is to understand the mechanism of HSV-1 latency at a molecular level.
Recently, we have made use of our knowledge of HSV latency to design vectors for long term foreign gene expression in the nervous system. Following infection with our HSV vector virus, -glucoronidase, a lysosomal storage enzyme, has been expressed for more than four months in PNS and CNS neurons of mutant mice lacking this enzyme. We are presently improving these vectors.
We are also developing HSV mutants for use in cancer therapy. HSV mutants lacking functions required for replicating in non dividing cells are being used to kill dividing tumor cells in a urine model of metastatic melanoma.
KEY WORDS:
Molecular virology; gene therapy; cancer therapy, neurons, HSV
