Human cytomegalovirus (HCMV) is a major cause of disease in the immunocompromised host. Infection of the central nervous system (CNS) is unusual in allograft recipients but is very common in patients with AIDS and in the newborn infant. Congenital HCMV infection is a leading cause of brain disease in infants and the most common non-familial cause of hearing loss in the US and western Europe. Although cellular immune response play a central role in the resolution of HCMV infection, antiviral antibodies have also been shown to influence the outcome of the infection. In animals with limited cellular immune responsiveness, antiviral antibodies may provide a margin of protection against extensive tissue dissemination and thus provide an important protective effector function. Small animal models have recapitulated many of the features of human infection with the exception of CNS infection. We have recently described infection of newborn mice with the murine CMV and consistently demonstrated infection of the CNS. We propose to utilize this model to investigate the role of antiviral antibodies in the pathogenesis of CMV infection of the CNS. Newborn animals, including transgenic mu chain knockout mice (antibody negative), will be infected, and the CNS infection will be characterized as the kinetics of virus replication, virus distribution within cells of the CNS, and CNS persistence. Once experimental parameters have been established, we will modify the infection by passively transferring antibodies contained in immune serum and/or monoclonal antibodies reactive with MCMV. In the final section of the proposal we will use passively transferred antibodies and antibody producing B lymphocytes to explore the hypothesis that antiviral antibodies not only limit virus dissemination the CNS but can restrict spread within the CNS. Theses studies should provide additional understanding of the mechanism of protective antiviral antibodies and provide a rational approach for the identification of protective antibody responses in humans.
