Mattes, FM; (2006) Virologic and immunological studies of human cytomegalovirus in transplant patients. Doctoral thesis , UCL (University College London).

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Abstract

Infection with human cytomegalovirus (HCMV), a member of the Betaherpesvirinae sub family is widespread. HCMV is a major pathogen in the fetus, transplant patients (solid and bone marrow) and patients infected with the human immunodeficiency virus (HIV). My first study analyzed the presence of HCMV, human Herpes Virus 6 (HHV 6) or human Herpes Virus 7 (HHV 7) by quantitative competitive polymerase chain reaction (QCPCR) in multiple organs collected from acquired immunodeficiency disease syn drome (AIDS) patients autopsy. The results showed that the presence of owl's eye in clusion bodies is highly specific for HCMV, but has a low sensitivity. My second study investigated T-cell mediated immunity as factor in controlling HCMV viral replication. Post renal transplantation, HCMV specific CD8 T-cells were enumer ated with 'tetrameric complexes' and the functional capacity of these cells was assessed by an interferon gamma (IFN-y) secretion assay. The results showed a higher frequency of specific CD8 T-cells in viremic patients and confirmed a functional deficiency in HCMV specific CD8 T-cells, present before during and after HCMV viremia. My third study analysed the data from a randomized controlled clinical trial, com paring intravenous (iv) ganciclovir (GCV) versus a combination of iv GCV plus foscar- net (PFA), each at half dose was performed, in liver, renal and bone marrow transplant (BMT) patients. The study showed no advantage for combination therapy compared to the monotherapy with iv GCV. Moreover, there was a trend in favour to GCV. All drug related toxicity was observed in the combination arm. Valganciclovir (VGCV) is an oral prodrug of GCV. An uncontrolled study compared the virological response to either iv GCV or oral valganciclovir (VGCV) in solid organ transplant (SOT) patients and showed that the virological response was identical for this preparation of GCV. In the the final part, I explored factors which predict the length of antiviral therapy required to become HCMV DNAemia negative. Univariable and multivariable regression models identified maximum virus load and baseline virus load (virus load at the begin ning of antiviral therapy) as the strongest predictors for the length of antiviral therapy in the HCMV immune experienced patient group. Overall, the results in this thesis address the complex interactions of HCMV with the host immune response and provide evaluations of methods used to measure these di rectly in patients.

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