THE IMMUNE-SYSTEM PREFERENTIALLY CLEARS THEILERS VIRUS FROM THE GRAY-MATTER OF THE CENTRAL-NERVOUS-SYSTEM

Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persi stence in the central nervous system (CNS) white matter and chronic de myelination similar to that observed in multiple sclerosis. We investi gated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe comb ined immunodeficient (SCID) and immunocompetent C.B-17 mice were infec ted with DAV to determine the kinetics, temporal distribution, and tro pism of the virus in CNS. In early disease (6 h to 7 days postinfectio n), DAV replicated with similar kinetics in the brains and spinal cord s of SCID and immunocompetent mice and in gray and white matter. DAV R NA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cor ds. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both ce llular and humoral immune responses decreased virus from the gray matt er; however, the cellular responses were more effective. SCID mice rec onstituted with splenocytes depleted of CD4(+) or CD8(+) T lymphocytes cleared virus from the gray matter but allowed replication in the whi te matter. These studies demonstrate that both neurons and glia are in fected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.