Coordination of the immune response to viral infection and disease in the brain is believed to involve bi-directional discourse between the immune system and the central nervous system (CNS). Progressive multifocal leukoencephalopathy (PML) is a neurodegenerative disease associated with a wide range of neurological impairments and neurobehavioral dysfunction including subcortical dementia. The human polyomavirus, JCV, which infects greater than 70% of the adult population, is the etiological agent of this disease. Infection with JCV occurs during childhood and the virus remains at the latent state with no apparent clinical symptoms. However, under immunosuppressed conditions, the virus enters the lytic cycle, and upon cytolytic destruction of glial cells, causes PML. The investigators hypothesize that the bi-modal interaction of immune and nervous systems promotes a regulatory mechanism in the JCV-infected cells which suppresses viral replication and maintains the virus in the latent state. Thus, the absence of this negative regulator in the infected cells leads to the reactivation of JCV and the development of PML. In support of this hypothesis the investigators have demonstrated that secretory factor from immune cells derived from non-PML individuals and that stimulate expression of a cellular protein in glial cells which binds to the viral origin of DNA replication, inhibit JCV DNA replication in glial cells. In this research project, the investigators propose to: (i) determine the immune cell induced negative regulatory factors from glial cells which are responsible for suppression of JCV replication, (ii) evaluate the ability of immune cells from PML patients in suppressing JCV DNA replication and inducing the activity of the candidate suppressor protein; and (iii) molecularly clone the gene encoding the suppressor protein and assess its expression and function in PML and non-PML individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH056105-02
Application #
2675532
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Project Start
1997-04-05
Project End
1998-11-10
Budget Start
1998-04-01
Budget End
1998-11-10
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129