Herpes simplex virus type 1 and the potential for gene transfer into the nervous system.
dc.contributor.author | Sternberg, Lawrence Robert | en_US |
dc.contributor.advisor | Glorioso, Joseph | en_US |
dc.contributor.advisor | Imperiale, Michael | en_US |
dc.date.accessioned | 2014-02-24T16:17:41Z | |
dc.date.available | 2014-02-24T16:17:41Z | |
dc.date.issued | 1993 | en_US |
dc.identifier.other | (UMI)AAI9409814 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9409814 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/103854 | |
dc.description.abstract | Although attenuated retroviral vectors provide an acceptable gene transfer vector system for many cells, the fact that cellular replication is a corequisite for transduction precludes their use with the post-mitotic cells of the nervous system. One strategy to overcome this limitation is a vector based on herpes simplex virus type 1 (HSV-1). HSV-1 can establish a transcriptionally active latent infection of a neuron without chromosomal integration. This thesis examined the effect that inactivation of a viral neurovirulence determinant (viral protein kinase (Us3)) had on pathogenesis then used the information to evaluate aspects of viral transcription relevant to the development of a neuronal gene transfer system. Results demonstrated that mutant strains of HSV-1 (KOS) defective in Us3 fail to spread significantly following targeted delivery into the eye or brain. Ultra structural analyses suggest that the defect results from inefficient assembly and release of progeny virus. Additional experiments demonstrated the Us3 defective virus establish long term latent infections of sensory and hippocampal neurons which are not associated with significant long term pathology or with the potential for reactivation. Subsequent studies of the transcriptional activity of the HSV-1 latency active promoter (pLAT) during latency by Us3 defective virus indicated that latency within hippocampal neurons is associated with a level of LAT transcription that is readily apparent only by reverse transcriptase PCR procedures. This finding contrasted with what was observed during latency within sensory neurons implying that enhancer elements will likely be required if pLAT is to prove useful for vigorous expression of foreign genes during CNS latency. Finally, studies which assessed whether the HCMV IE1 promoter (pIE1) was transcriptionally active from the context of the HSV-1 genome indicated that the promoter was highly active during acute infection but inactive during latency. Taken together, these results suggest that a greater understanding of the cellular transcriptional factors and/or the physical state of the latent viral genome will be required to produce a functional CNS vector. | en_US |
dc.format.extent | 139 p. | en_US |
dc.subject | Biology, Neuroscience | en_US |
dc.subject | Biology, Microbiology | en_US |
dc.subject | Engineering, Biomedical | en_US |
dc.title | Herpes simplex virus type 1 and the potential for gene transfer into the nervous system. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Microbiology and Immunology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/103854/1/9409814.pdf | |
dc.description.filedescription | Description of 9409814.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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