MHV infection of the CNS: Mechanisms of immune-mediated control

Mice infected with neurotropic strains of mouse hepatitis virus (MHV) clear infectious virus; nevertheless, viral persistence in the central nervous system (CNS) is associated with ongoing primary demyelination. Acute infection induces a potent regional CD8(+) T-cell response. The high prevalence of virus specific T cells correlates with ex vivo cytolytic activity, interferon-gamma (IFN-gamma) secretion and efficient reduction in virus. Viral clearance from most cell types is controlled by a perforin dependent mechanism. However, IFN-gamma is essential for controlling virus replication in oligodendrocytes. Furthermore, CD4(+) T cells enhance CD8(+) T-cell survival and effectiveness. Clearance of infectious virus is associated with a gradual decline of CN8(+) T cells; nevertheless, activated T cells are retained within the CNS. The loss of cytolytic activity, but retention of IFN-gamma secretion during viral clearance suggests stringent regulation of CD8(+) T-cell effector function, possibly as a means to minimize CNS damage. However, similar CD8(+) T-cell responses to demyelinating and non demyelinating JHMV variants support the notion that CD8(+) T cells do not contribute to the demyelinating process. Although T-cell retention is tightly linked to the presence of persisting virus, contributions to regulating the latent state are unknown. Studies in B-cell-deficient mice suggest that antibodies are required to prevent virus recrudescence. Although acute JHMV infection is thus primarily controlled by CD8(+) T cells, both CD4(+) T cells and B cells make significant contributions in maintaining the balance between viral replication and immune control, thus allowing host and pathogen survival.