The human polyomavirus, JCV, causes a demyelinating disease in immune compromised individuals, progressive multifocal leukoencephalopathy (PML). PML is a substantial neurological complication in AIDS patients, occuring in 8% of all cases. PML is the AIDS defining illness in almost 1% of AIDS cases. Although in the past PML was a rare disease, it now represents a large number of neurological disease and is considered on the increase by recent statistics from the CDC. JC Virus was orignially thought to be strictly neurotropic, infecting only macroglial cells derived from the human brain. However, our results have now shown that there is a firm link between lymphoid and glial cells in the pathogenesis of JCV infection leading to demyelination in the human brain. The data indicate that the same viral genotype which is found in brain tissue of PML patients originates from an initial lymphoid cell infection. The molecular similarities for JCV gene expression between cells of the nervous and immune systems directly correlated with the expression of the NF-1 class D family of DNA binding proteins which function for viral transcription. We have cloned the gene for NF-1/D from human brain which is highly expressed. There appears to be a close association between susceptibility of infection to JCV and expression of this DNA binding protein. We have made expression vectors for all four class members of the NF-1 family and are making cell lines which uniquely express each one using the JEG human cell which has no baseline level of NF-1 expression. We have been able to over express NF-1/D in human neurons differentiated from human CNS progenitor cells that are not susceptible to infection since these cells do not express competent levels of NF-1/D. The NF-1/D over expressing neurons however are susceptible to JCV infection, confirming the necessary regulatory function of this transcription factor. We also constructed JC virion like particles using baculovirus expressed viral VP1 protein and used these viral like particles as antigens for the quantitation of antibody levels in the human population. We have determined that individuals, throughout the world, develop antibodies to JCV and the other human polyomavirus,BKV,which are not cross reacting. There also does not seem to be serologic cross reactivity to the primate SV 40 virus thought to be associated with neoplasms in humans due to their possible introduction as a contaminante in the original polio virus vaccine. We are collaborating with the FDA to re-examine the significance of the circulation of the primate polyomaviruses including JCV, BKV, and the monkey SV40, a contaminant in early human vaccines. Advancing technologies allows us to direct attention to possible therapies for PML in an increasing immune suppressed population. Currently we are the laboratory support for a clinical trial of intraparenchymal administration of ARA-C in AIDS patients with PML using convection enhanced delivery of ARA-C. We are also collaborating with the Johns Hopkins University Bloomberg School of Public Health and Hygiene and the Cancer Epidemiology Department to assess the prevalence of viral genome sequences in human brain derived tumors. We have investigated over 200 well characterized tumor tissues, mostly astrocytomas, in a double blind laboratory study. We will examine over 300 additional tumor tissues before the study is considered statistically advanced for a conclusion can be made. As a CLIA certified laboratory we have also participated in collaborative, viral diagnostic work that identified the human BK polyomavirus assoicated with allograft recipients. In one case published in the New England Journal of Medicine, we detected BK virus in endothelial cells that caused a vasculopathy which ultimately led to the death of the patient. This was the first description of such a pathology and has directed new treatment regimens in kidney transplant patients with evidence of polyomavirus infection.
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