MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

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The laboratory has participated in a Phase II clinical trial for treatment of AIDS patients with the demyelinating disease, PML. We had previously demonstrated the effectiveness of the nucleotide analogue, cytosine arabinoside (ARA-C) to block replication of the viral DNA. Concentrations of ARA-C used were not toxic to the human glial cells in culture. Currently 38 AIDS patients with biopsy proven PML (the laboratory confirms the diagnosis using in situ DNA hybridization to detect viral DNA) have been enrolled in the study. We have examined the peripheral blood and cerebrospinal fluid from these patients as treatment proceeds. In almost all cases, viral DNA has been found in the blood. In several samples, the viral DNA was identified in the B lymphocyte population and not T cells. This observation is consistent with previous clinical samples of B cell infection in bone marrow and spleen. The treatment protocol will continue until a maximum of 90 patients are enrolled or two years have elapsed. It is too early in the study to determine efficacy of the drug. Molecular biology studies are now linking B and glial cell susceptibility to JCV infection at the transcriptional level. A member of the transcription factor family, NF-1, appears to be highly expressed in found by Northern blot analysis in B cell lines that allow JCV to multiply. Further analysis of the NF-1/AT1 clone transfected into non- permissive cells is being done. The NF-1 factor, however, is not increased in its activity with cytokine stimulation using TNF-alpha or IL-1 beta. These cytokines stimulate the NF-kB transcription factor which is essential for HIV-1 multiplication in glial cells. It is not likely that JCV uses NF-kB for transcription nor is it likely that JCV infection is augmented by cytokines.