Bowen, Elizabeth Frances; (1997) Studies of the natural history of human cytomegalovirus infection in the HIV infected host. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis examined the relationship between human cytomegalovirus (HCMV) infection and HCMV disease occurrence in patients co-infected with HIV. HCMV PCR was used to screen asymptomatic patients with low CD4 counts for their risk of developing HCMV disease. Patients who were HCMV PCR positive had a 21 fold increase in risk of HCMV disease compared to those who remained HCMV PCR negative. I suggest that PCR positive patients are a high risk group in whom controlled trials of pre-emptive therapy should be conducted. The quantity of HCMV present in blood (HCMV load) at the time of diagnosis of retinitis was found to have important implications.Firstly, if left untreated HCMV load continued to increase, HCMV retinitis progressed and HCMV disease occurred in other organs. Secondly, patients with an HCMV load>5 log10 genomes/ml blood at diagnosis of retinitis responded less well to ganciclovir induction therapy and had a shorter time to first progression of retinitis. Thirdly, there was a significant association between high HCMV loads at retinitis presentation and reduced survival. Whilst receiving maintenance therapy 80% of patients had at least one episode of retinitis progression which occurred mostly in the absence of detectable PCR-viraemia. I suggest this was likely to be due to local reactivation of virus in the retina. Patients who did become PCR positive during maintenance therapy all had an episode of retinitis progression and had a significantly higher risk of developing other HCMV disease. Patients who were PCR positive were also more likely to develop mutations in the UL97 gene conferring ganciclovir resistance. I developed a point mutation assay for screening patient samples for the presence of the five most common UL97 resistant mutations. These results were then used to study the viral fitness of different UL97 mutants and hence, estimate the in vivo generation time of HCMV. I expressed one of these UL97 mutants (L595F) in a recombinant baculovirus expression system in preparation for functional studies. All studies conducted in this thesis had gained full approval from the Royal Free Hospital School of Medicine Ethics Committee.

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