MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

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Investigations of JCV~induced progressive multifocal leukoencephalopathy (PML) are being carried out on clinical specimens, in tissue culture, and biochemical analysis of host cells. JCV DNA was detected in peripheral lymphocytes in more than 90% of PML patients using PCR analysis. Many of these patients had AIDS as the underlying immune disorder. In HIV~1 seropositive individuals without PML, more than 50% of the individuals were found to have JCV in their peripheral lymphocytes. This later group would be at risk to develop PML in the future. JCV DNA was found in bone marrow and kidney tissue three years prior to the onset of PML in a patient with Wiskott~Aldrich syndrome, and latter found in bone marrow and brain samples taken at the time of autopsy. This latter case suggests that JCV can be latent in cells in bone marrow, and in addition, with the finding of JCV in peripheral lymphocytes, suggest that JCV could be spread to the CNS by a hematogenous route. Expression vectors under the control of the prototype Mad~1 or "brain" type strain Mad~8 regulatory region are being constructed to examine what tissue and cell type can influence JCV gene expression. Both chloramphenicol acetlytransferase and beta- galactosidase expression vectors are used in transfection studies to answer the question of tissue specific and cell specific expression of JCV. Biochemical analysis of nuclear proteins from human fetal brain and human B cells were studied to determine if similar proteins were involved in JCV gene expression in these tissues. Nuclear proteins from both these human cell lines were able to specifically interact with identical nucleotide sequences in the JCV regulatory region. One of these protein factors was identified as a nuclear factor~1 (NF~1) protein and the other a c~Jun like factor. Within the regulatory region of JCV, there were several NF~1 protein binding sites. The c~Jun binding sites were either adjacent or overlapped all the NF~1 binding sites located in the regulatory region. A similar association of putative NF~1 and activator protein binding sites was found in many other genes expressed in the brain. These results suggest that human brain cells and B cells may contain similar factors which can regulate the expression of JCV in these tissues.