An analysis of the neurotropic behavior of Gross murine leukemia virus and the role of impaired antiviral immunity in persistent viral infection of the murine central nervous system
Recently, a novel form of persistent viral infection of the murine CNS was observed following exposure of newborn mice to Gross murine leukemia virus (GMuLV). Virus infected cells were specifically localized to the CNS white matter. Additionally, infected animals failed to exhibit any signs of virus induced neuropathology. The purpose of this project was to further characterize the neurotropic behavior of GMuLV and to analyze the mechanism(s) involved in the persistence of the virus within the CNS. GMuLV infection of the CNS requires that mice be exposed to virus either in utero or within the first 24 hours after birth. This is not dependent on the route of inoculation. Further, susceptibility to CNS infection does not appear to be genetically regulated. Mice expressing different background genes and MHC haplotypes are equally susceptible to virus infection. The target cell within the CNS exists within the oligodendrocyte lineage and may be the bipotential cell that gives rise to oligodendrocytes and type-2 astrocytes. Neonatal exposure to GMuLV also results in a profound inhibition of the virus-specific T and B cell responses of adult animals. Mice exposed to virus as neonates exhibit a marked depression in virus-specific T cell function as measured by the virtual absence of in vivo delayed type hypersensitivity responses and in vitro proliferative responses to virally infected stimulator cells. Furthermore, serum obtained from neonatally treated mice failed to either immunoprecipitate viral proteins or neutralize virus in an in vitro plaque assay, suggesting the concurrent induction of a state of B cell hyporesponsiveness. Immunohistochemical analyses show that the sites of GMuLV infection in the CNS are devoid of MHC expression, although transplantation of GMuLV-infected brain tissue to the kidney capsules of immunocompetent mice induces an inflammatory graft infiltrate. These results indicate that persistent GMuLV infection of the CNS is linked to both impaired lymphocyte and antigen presenting cell activity. Finally, the replication of GMuLV within both stromal and lymphocytic cells of the neonatal thymus suggests that thymic education plays a key role in the induction of immunologic nonresponsiveness to viruses.
Korostoff, Jonathan Mark, "An analysis of the neurotropic behavior of Gross murine leukemia virus and the role of impaired antiviral immunity in persistent viral infection of the murine central nervous system" (1991). Dissertations available from ProQuest. AAI9125694.