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Title: Investigation of factors involved in herpes simplex virus type 1 pathogenesis
Author: Grey, F. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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The mouse model has been extensively used in studies of HSV pathogenesis and has led to a greater understanding of many aspects of the virus life cycle and viral replication in vivo. The current study makes use of the mouse model to investigate two aspects of viral pathogenesis. The initial project concerns viral resistance to the antiviral drug Aciclovir (ACV) and the pathogenesis of a resistant clinical isolate. The aim of the second project was to investigate the effects of disrupting antigen presentation by MHC class I on the replication and pathogenesis of HSV-1. Aciclovir is a highly effective drug in the treatment of herpetic infections. Its effectiveness, however, is undermined by the emergence of resistance virus isolates that can cause serious disease in immunocompromised patients. In the majority of cases resistance occurs through a mutation that disrupts the TK gene of HSV and is normally associated with attenuation of neurovirulence. In this study a clinical isolate resistant to ACV (4B) was found to display a high level of neurovirulence despite a double G insertion mutation that would theoretically disrupt all TK activity. Following inoculation of the mice the virus was able to replicate efficiently in dorsal root ganglia during acute infection and was able to reactivate from latency. Furthermore, plaque purified isolates of 4B uniformly expressed a very low level of TK activity. Disruption of the TK gene of 4B led to a loss of the low level of TK activity and a loss in the ability to replicate in the ganglia of mice and to reactivate from latency. Further investigation showed that the ability of isolate 4B to replicate in the nervous system of mice was due to the virus gaining an additional G residue, rescuing the original frameshift mutation and allowing the virus to express wild type levels of TK. The neurovirulence associated with 4B is therefore due to phenotypic reversion. The immune response of the host plays an important role in shaping the pathogenesis of HSV. To counteract the antiviral effects of the immune system HSV encodes a number of genes involved in immune evasion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available