The pathogenesis of such human diseases as multiple sclerosis, subacute sclerosing panencephalitis and the acquired immunodeficiency syndrome may include viral latency of persistence with subsequent reactivation in the central nervous system (CNS). Little is known about these processes in either humans or in laboratory animals. A mouse model has been developed in which 40-90% of suckling C57BL/6 mice infected with mouse hepatitis virus, strain JHM (MHV-JHM) develop a clinically evident, demyelinating encephalomyelitis after a latent period of 3-8 weeks. Viral antigen can be detected in all mice, whether symptomatic or not, but virus can only be isolated from mice with clinical disease. The virus isolated from mice with the late onset demyelinating disease has been shown to be identical to the infecting strain, suggesting that a defect in the host immune system may be important for viral persistence and reactivation. This model should be useful for answering some of the questions concerning the relationship of viral persistence and reactivation and the later development of demyelination. The specific objectives that will be addressed in this research plan are: 1) To determine the entry sites of MHV-JHM into the mouse CNS after different routes of inoculation. To determine the anatomic sites for viral persistence and reactivation in the mouse CNS. This will be accomplished using in situ hybridization and immunohistochemical techniques. 2) To determine the cell-mediated immune response in mice persistently infected with MHV-JHM. For this purpose, recombinant vaccinia virus vectors capable of expressing MHV-JHM proteins will be developed and used in cell proliferation and cytotoxic T cell assays. The specific immunogenic sites on each protein will be determined. The cell-mediated immune response will also be studied with adoptive transfer experiments. 3) To determine the role of nonstructural proteins in viral replication and persistence. The cellular localization, kinetics of synthesis and function of p28, a protein encoded by the presumptive viral polymerase gene, will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS024401-04
Application #
3408954
Study Section
Experimental Virology Study Section (EVR)
Project Start
1987-01-01
Project End
1994-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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