Investigation of herpes simplex virus and cytomegalovirus infection in the immunocompromised host

The remit of this thesis was to examine the role of HSV and CMV infections in patients with AIDS and in bone marrow transplant recipients. PCR was used to monitor the efficacy of a novel drug, valaciclovir, in ADDS patients at risk of CMV disease. Valaciclovir was found to be effective at reducing the excretion of CMV in patients who were baseline PCR-positive, and in patients with advanced HIV disease, the drug delayed the onset of CMV end-organ disease. A confirmatory assay based on an oligonucleotide probe conjugated to alkaline phosphatase was used to evaluate a number of samples from the ACTG 204 study that produced non-specific results using PCR. Quantitative PCR was used to retrospectively monitor fluctuations in viral load in the blood of BMT recipients. When the relative contribution to CMV disease of risk factors such as recipient CMV serostatus, virus load, T-cell depletion, and acute-GvHD was assessed, virus load was found to be the most significant risk factor for disease. In univariate statistical analysis, recipient seropositivity was also identified as a significant risk factor for CMV disease. Immune modulation and the dynamics of virus clearance from the blood were assessed in order investigate the efficacy of antiviral intervention with ganciclovir. Finally, nine herpes simplex vims isolates from 3 HIV patients and one BMT patient, which were resistant to ACV in vitro, were subjected to phenotypic and genotypic analyses. All the viruses were found to be TK deficient, and genotypic analysis showed the presence of a number of mutations including single base deletions and coding substitutions

Modelling cytomegalovirus replication patterns in the human host: factors important for pathogenesis

Human cytomegalovirus can cause a diverse range of diseases in different immunocompromised hosts. The pathogenic mechanisms underlying these diseases have not been fully elucidated, though the maximal viral load during infection is strongly correlated with the disease. However, concentrating on single viral load measures during infection ignores valuable information contained during the entire replication history up to the onset of disease. We use a statistical model that allows all viral load data sampled during infection to be analysed, and have applied it to four immunocompromised groups exhibiting five distinct cytomegalovirus-related diseases. The results show that for all diseases, peaks in viral load contribute less to disease progression than phases of low virus load with equal amount of viral turnover. The model accurately predicted the time of disease onset for fever, gastrointestinal disease and pneumonitis but not for hepatitis and retinitis, implying that other factors may be involved in the pathology of these diseases