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Title: The role of productive replication in the pathogen of murine gammaherpes virus-68
Author: Barnes, A. G. C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Murine gammaherpesvirus-68 (MHV-68) is natural pathogen of small free living rodents. Like Epstein-Barr virus, MHV-68 is B-cell tropic with respect to latency and sensitive to the anti-viral acyclovir (ACV). The aim of this project was to evaluate the potency of a new anti-viral called 2'-deoxy-5-ethyl-β-4'-thiouridine (4'-s-EtdU) as an inhibitor of MHV-68 replication both in vitro and in vivo. Finally to utilise to the anti-viral activity of 4'-s-EtdU, to be able to study disease associated with gammaherpesvirus latency in immunocompromised mice, without the complications associated with lytic virus replication. The potency of 4'-s-EtdU as an inhibitor of the lytic replication was determined to be 15 times greater than ACV by EC50 assay, giving a value of 0.13μM (35ng/ml). Treatment of infected cell lines led to the elimination of detectable productive viral replication. However, virus genomic DNA, which remained capable of reactivation after treatment withdrawal, was not eliminated. Not only was this true for cell lines which MHV-68 is known to establish latency, but also cell lines previously known only to support lytic replication. The nature of the viral persistence appeared different for the different cell lines both with respect to virus reactivation after withdrawal of treatment and to the spontaneous generation of 4'-s-EtdU resistant viral variants. The data leads to the possibility of MHV-68 being capable of episomal maintenance whilst in a perpetual state of attempted productive replication. Spontaneously arising 4'-s-EtdU resistant virus variants were cloned and isolated and found to remained sensitive to the anti-viral effects of ACV. However, further characterisation of these viral variants was not undertaken. Treatment of mice with 4'-s-EtdU (0.3mg/ml in drinking water) from 3 days post infection (in), rapidly eliminated productive virus replication in the lung tissue, but failed to prevent the establishment and long-term maintenance of viral latency in the lymphoid compartments. Treatment also failed to prevent the post acute splenomegaly commonly observed in MHV-68 infected mice. However, prophylactic treatment of mice prior to infection (in), did prevent virus dissemination to the spleen as well as preventing splenomegaly. Viral DNA remained absent from the spleen for as long as treatment was maintained, up to 54 days post infection, as determined by both co-cultivation assay and nested PCR.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available