CHRONIC VIRAL INFECTIONS--MOLECULAR BIOLOGY OF HUMAN JC VIRUS

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Our current results emphasize the molecular interactions of the JC virus (JCV) with glial cells of the human brain. Progress has been made in understanding the progression of the JCV infection which leads to a demyelination of the central nervous system of immunodeficient patients. At the molecular level we have found that JCV early gene transcription is regulated by glial cell specific proteins which recognize the DNA sequences in the JCV regulatory region. In contrast, JCV DNA replication is regulated by specific proteins which are found in a wide range of primate cells. We have provided further evidence of the accuracy of in situ DNA:DNA hyridization as a laboratory diagnosis for the presence of JCV DNA in brain biopsy specimens from patients with progressive multifocal leuko-encephalopathy (PML). Clinical examinations, histopathology and electron microscopic identification correlated in all cases to positive hybridization results, thus indicating that hybridization tests are able to identify JCV as the cause of PML. Furthermore, viral DNA from a case study of PML was isolated and its DNA partially sequenced. The isolated virus was identified as a Mad-4 strain of JCV. From our continuing animal studies, a transplantable owl monkey astrocytoma was found in culture to release infectious JC virus. Only about 30% of the viable tumor cells in culture released virus indicating the establishment of a persistent carrier culture. The released virus designated JCV 586 was found by DNA sequencing to contain a 19 bp deletion in the second tandem repeat of the viral regulatory region, thus identifying the virus as a Mad-4 strain. In contrast to our results with the JCV Mad-1 strain, the JCV 586 T protein binds the host cellular p53 protein (a nuclear oncogene). Furthermore, monoclonal antibodies which bind epitopes at the amino terminus and the carboxy terminus of the SV 40 T protein, also recognize the JCV 586 T protein, indicating some structural homology between the JCV 586 and SV 40 T proteins.