Molecular Pathogenesis Of Jc Virus &Progressive Multifo

Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

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, its incidence is high in immune compromised patients like AIDS and allograft recipients. 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 susceptible 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. We have made a unique human brain derived, multipotential progentior cell line that can differentiate to either neurons or glial cells. 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 as we have shown in the past in hematopoietic cells. We also constructed JC virion like particles from the VP1 protein and used these viral like particles as antigens for the quantitation of antibody levels in the human population. Working with the Johns Hopkins School of Public Health and Hygiene, we have determined that brain tumor patients in a very large cohort study have the same titer and seropositivity as non-tumor patients to JCV as well as the other human polyomavirus,BKV, and that these antibodies are not cross reacting. Advancing technologies allows us to direct attention to possible therapies for PML in an increasing immune suppressed population. Currently we are continuing 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 300 well characterized tumor tissues, mostly glioblastomas and astrocytomas, in a double blind laboratory study with only a few tumor tissues showing the presence of the human polyomavirus genomes. 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. We are also testing the efficacy of a group of drugs to block JCV and BKV replication in a quantitative assay as preclinical evidence for advancement to human clinical trials.