Perrons, Christopher John; (2001) Papovaviruses in humans. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Papovaviruses are a family of small, non-enveloped viruses of similar morphology that contain circular double-stranded DNA. They are divided into the two genera polyomaviruses and papillomaviruses on the basis of genome size and biological properties. Human polyomaviruses comprise two agents, JC virus (JCV) and BK virus (BKV). After initial infection both persist indefinitely but are usually only associated with disease in immunosuppressed patients. JCV and BKV, together with simian polyomavirus simian virus 40 (SV40), have been associated with central nervous system disease. In particular JCV is associated with the demyelinating disease progressive multifocal leukoencephalopathy (PML), once considered a rare complication of immunosuppression in transplant recipients. With the advent of the AIDS pandemic, PML became of increasing importance in HIV-infected individuals. Human papillomaviruses (HPV) comprise a large group of inter-related but different viral genotypes. Some of these are termed low risk, causing warts at various sites in the body. Others, termed high risk, are aetiologically linked with squamous cell carcinoma, principally being implicated in the development of cervical carcinoma. This thesis describes molecular methods developed for investigation of human papovaviruses. The initial part describes the development of molecular techniques for the detection and analysis of neurotropic polyomavirus sequences in samples from immunosuppressed patients. These methods were used to examine the correlation between polyomaviruses and clinical disease and to evaluate the use of molecular techniques in the diagnosis of PML. Nested PCR assays for JCV, BKV and SV40 were developed to determine the prevalence of polyoma sequences in CSF and brain samples. JCV was the only polyomavirus to have a direct correlation with PML. Detection of JCV DNA in the CSF of patients with a clinical diagnosis of PML was found to be 100% specific and 83% sensitive. Studies also looked at polyomaviruses present at other sites of the body and a comparison made of their genome sequences. The use of molecular techniques were shown to be of great value in diagnosis of PML and the possible monitoring of the treatment of PML. However the introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV-infected individuals has resulted in a dramatic reduction in the number of cases of PML in the UK and as a consequence, the intended study of clinical intervention was aborted. The later parts of this thesis describes the development and application of similar molecular techniques for the detection and typing of HPV. PCR amplification was used to determine the prevalence of HPV at the cervix and amplicons were typed using a reverse hybridisation line probe assay. HPV DNA was detected in 80% of cervical smears taken from patients, often with multiple infection, attending a routine colposcopy clinic. Twenty one genotypes were identified in these samples confirming a need for methods to distinguish not only between high risk and low risk types but also between different genotypes infecting patients in this clinic.

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