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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Major, Eugene O (2009) Progressive Multifocal Leukoencephalopathy in Patients on Immunomodulatory Therapies. Annu Rev Med :
Linda, Hans; von Heijne, Anders; Major, Eugene O et al. (2009) Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 361:1081-7
Major, Eugene O (2009) Reemergence of PML in natalizumab-treated patients--new cases, same concerns. N Engl J Med 361:1041-3
Bohl, Daniel L; Brennan, Daniel C; Ryschkewitsch, Caroline et al. (2008) BK virus antibody titers and intensity of infections after renal transplantation. J Clin Virol 43:184-9
Houff, Sidney A; Berger, Joseph; Major, Eugene O (2008) Response to Linberg et al. Natalizumab alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients. J Neuroimmunol 199:160-161
Roseti, Livia; Facchini, Andrea; De Franceschi, Luciana et al. (2007) Induction of original phenotype of human immortalized chondrocytes: a quantitative gene expression analysis. Int J Mol Med 19:89-96
Ravichandran, Veerasamy; Jensen, Peter N; Major, Eugene O (2007) MEK1/2 inhibitors block basal and transforming growth factor 1beta1-stimulated JC virus multiplication. J Virol 81:6412-8
Ravichandran, Veerasamy; Major, Eugene O (2006) Viral proteomics: a promising approach for understanding JC virus tropism. Proteomics 6:5628-36
Li, Jongming; Melenhorst, Jos; Hensel, Nancy et al. (2006) T-cell responses to peptide fragments of the BK virus T antigen: implications for cross-reactivity of immune response to JC virus. J Gen Virol 87:2951-60
Yousry, Tarek A; Major, Eugene O; Ryschkewitsch, Caroline et al. (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354:924-33

Showing the most recent 10 out of 41 publications