Sindbis virus (SV) is an alphavirus that infects neurons and causes acute encephalomyelitis in mice. Non-fatal SV infection of the central nervous system (CNS) of weanling mice elicits a well-characterized immune response and provides a model system for studying mechanisms by which virus is cleared from neural cells. Mice with severe combined immunodeficiency (SCID) cannot clear virus and these mice develop persistent infection. The applicant has shown by passive transfer experiments that antibody (Ab) is the primary mechanism by which infectious virus is cleared from the CNS. Ab-mediated control of intracellular virus replication is independent of complement and leukocytes, is noncytolytic and requires cross-linking of the E2 glycoprotein on the surface of the infected cell. Downregulation of SV replication is associated with improved Na+K+ATPase-dependent control of cation flux and results in restoration of host protein synthesis and response to type 1 interferons (IFNs). In mice this noncytotoxic mechanism for control of virus replication results in persistence of viral RNA in the CNS and long-term local production of antiviral Ab by B cells in the CNS. In the current application, the applicant proposes to determine the mechanism by which Ab controls intracellular virus replication in vivo and in vitro and the role of IFN in this process through the following specific aims: (1) To define the required specificity and cellular localization of antibody for effective control of intracellular SV replication; (2) To determine the mechanism by which antibody to the E2 glycoprotein of SV restores Na+K+ATPase function and controls intracellular virus replication; (3) To determine the relative roles of antibody, interferon and T cell cytokines for in vivo control of SV replication.
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