To investigate the mechanism by which viruses are cleared from neurons in the central nervous system, we have utilized a mouse model involving infection with a neurotropic variant of mouse hepatitis virus (OBLV60). After intranasal inoculation, OBLV60 grew preferentially in the olfactory bulbs of BALB/c mice. Using in situ hybridization, we found that viral RNA localized primarily in the outer layers of the olfactory bulb, including neurons of the mitral cell layer. Virus was cleared rapidly from the olfactory bulb between 5 and 11 days. Athymic nude mice failed to eliminate the virus, demonstrating a requirement for T lymphocytes. Immunosuppression of normal mice with cyclophosphamide also prevented clearance. Both CD4+ and CD8+ T-cell subsets were important, as depletion of either of these subsets delayed viral clearance. Gliosis and infiltrates of CD4+ and CD8+ cells were detected by immunohistochemical analysis at 6 days. The role of cytokines in clearance was investigated by using an RNase protection assay for interleukin-la (IL-la), IL-10i, IL-2, IL-3, IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-o), TNF-I, and gamma interferon (IFN-,y). In immunocompetent mice there was upregulation of RNA for IL-la, IL-11", IL-6, TNF-a, and IFN-y at the time of clearance. Nude mice had comparable increases in these cytokine messages, with the exception of IFN-y. Induction of major histocompatibility complex class I (MHC-I) molecules on cells in infected brains was demonstrated by immunohistochemical analyses in normal and nude mice, suggesting that IFN-y may not be necessary for induction of MHC-I on neural cells in vivo.

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A cardinal feature of the biology of lymphocytic choriomeningitis virus (LCMV) is its ability to establish persistent infections in mice. Persistence is usually established by infection of the mouse during the in utero or neonatal period. Susceptibility can be extended to the adult by treatment with immunosuppressive agents or by infection with immunosuppressive strains of LCMV. In this study we investigated the capacity of passively acquired anti-LCMV antibodies to prevent the establishment of persistence in both neonatal and adult mice. Suckling BALB/c mouse pups nursed by mothers immunized against LCMV before pregnancy had higher survival rates following infection than controls and withstood challenge doses of up to 400 PFU without becoming persistently infected. To establish that maternal antibody alone and not maternally derived T cells provided this protection, nonimmune mothers were infused with monoclonal anti-LCMV neutralizing antibodies within 24 h after delivering their pups. Pups nursing on these passively immunized mothers were resistant to persistent LCMV infection. The establishment of persistence in adult BALB/c mice by the immunosuppressive, macrophage-tropic LCMV variant, clone 13 was also prevented by prophylactic treatment with anti-LCMV monoclonal antibodies. However, the protection afforded by passively acquired antibody was found to be incomplete if the recipients lacked functional CD8 ؉ T cells. While 65% of neonatal athymic (nu/nu) mice nursed by immune nu/؉ dams resisted low-dose viral challenge (25 PFU), the majority of nude pups challenged with high doses of virus (100 PFU) became persistently infected. Also, protection was incomplete in ␤ 2-microglobulin knockout mice, which lack functional CD8 ؉ T cells, suggesting that a cooperative effect was exerted by the combination of neutralizing antibody and endogenous T cells. These results indicate that antibodies provide an effective barrier to the establishment of persistent infections in immunocompetent mice and reaffirm that vaccines which induce strong humoral responses may provide efficient protection against arenavirus infections.

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