Archetype and Rearranged Non-coding Control Regions in Urothelial Bladder Carcinoma of Immunocompetent Individuals.

BACKGROUND: Polyomaviruses (PyVs) are potential transforming viruses. Despite their involvement in human tumours still being debated, there is evidence to suggest a role for PyVs in bladder carcinoma (BC). Therefore, a possible association between PyVs and BC was investigated. MATERIALS AND METHODS: Urine, blood and fresh bladder tissue specimens were collected from 29 patients with BC. PyV prevalence, non-coding control region (NCCR) organization and genotypic analysis were assessed. RESULTS: Data showed a significant prevalence of John Cunningham (JC) PyV in BC tissues and in urine with respect to BKPyV, while simian virus 40 was not revealed. A BKPyV rearranged NCCR sequence was isolated, whereas a JCPyV archetypal structure was consistently retained. A prevalence of European genotypes was observed. CONCLUSION: Our data would suggest a JCPyV involvement in cancer progression and a BKPyV association with BC pathogenesis in immunocompetent patients. However, further work is necessary to better understand the exact role of PyVs in urothelial carcinogenesis.

Analysis of the transcriptional control region of JC polyomavirus in cerebrospinal fluid from HIV-negative patients with progressive multifocal leucoencephalopathy.

The human polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). JCV has a hyper-variable non-coding transcriptional control region (TCR), which contains the origin of replication and the promoters of viral transcription and replication. The archetype form of TCR-JCV is frequently found in the urine and kidneys of healthy and immunocompromised subjects. However, the rearranged forms, possibly generated by deletion and duplication of segments of the archetype sequence, are found in the peripheral blood, cerebrospinal fluid (CSF), and brain of PML patients. Most experience on this setting has come from the human immunodeficiency virus (HIV) pandemic. Little has been described on the JCV-TCR sequences from PML-HIV-negative patients affected by other immunosuppressive disorders. The aim of this study was to analyze the JCV-TCR detected in CSF samples from 12 HIV-negative immunosuppressed patients suffering from PML and to investigate the possible role of genomic organization in the different incidences of PML in HIV-positive and HIV-negative patients. The results confirm that the JCV-TCR rearrangements play a crucial role in the development of PML, although they do not account for the higher frequency of the disease in HIV infection. These data support the hypothesis that, independently of the rearrangement patterns of JCV-TCR, the direct action of HIV together with other as yet unidentified cellular determinants can be a key to explaining the high rate of PML in HIV infection with respect to other underlying immunosuppressive conditions.

Identical rearranged forms of JC polyomavirus transcriptional control region in plasma and cerebrospinal fluid of acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by the human polyomavirus JC (JCV). JCV has a hypervariable noncoding transcriptional control region (TCR) that spans the origin of replication of the JCV genome through to the first ATG start codon for late gene transcription. The archetype form of TCR is frequently found in the urine and kidneys of healthy and immunocompromised subjects. However the rearranged forms, whose prototype is Mad-1, possibly generated by deletion and duplication of segments of the archetype sequence, are found in the brain and cerebrospinal fluid (CSF) of PML patients. In this study the authors compared JCV TCR detected in paired CSF, plasma, and urine samples of 11 acquired immunodeficiency syndrome (AIDS) patients affected by PML to try to determine where the rearranged JCV TCRs are selected. In one patient, it was also possible to amplify and sequence the TCR in the brain and lymphocytes. Moreover, in 5/11 patients, the CSF, plasma, and urine samples corresponding to 2 months after PML development were available; and in another patient, it was possible to sequence the TCR in plasma and lymphocytes sampled 8 months before the onset of PML. The presence of the same TCR sequences in all the CSF and plasma samples taken from individual patients could strengthen the hypothesis that the blood is a compartment where JCV may replicate and undergo rearrangement of the TCR. This further supports the hypothesis that JCV reaches the brain by a hematogenous route and indicates that the JCV TCR sequences detected in plasma could be used as an early marker of JCV pathogenicity before the clinical appearance of PML in immunocompromised patients.