Control of Alphavirus Replication in the Nervous System

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DESCRIPTION (provided by applicant): Sindbis virus (SV) is an alphavirus that infects neurons and causes acute encephalomyelitis in mice. Outcome is age-dependent and newborn mice develop fatal disease while weanling mice develop a well-characterized immune response that leads to recovery from infection and provides a model system for studying the mechanisms by which virus is cleared from neurons. Mice with severe combined immunodeficiency (SCID) do not develop an SV-specific humoral or cellular immune response and cannot clear virus. We have shown that infectious virus can be cleared from the central nervous system (CNS) by antibody (Ab) to the SV E2 glycoprotein and can be cleared from spinal cord motor neurons, but not cortical or hippocampal neurons by interferon (IFN)?. Both of these processes of SV clearance involve mechanisms that do not damage infected neurons. Ab-mediated control of intracellular virus replication is independent of complement and leukocytes and requires cross-linking of the E2 glycoprotein on the surface of the infected cell. Down-regulation of SV replication is associated with improved Na???dependent cation flux, inhibition of virus budding, restoration of host protein synthesis and response to IFN-???. IFN- mediated clearance is associated with transient increases in viral RNA and protein synthesis with a decreased ratio of genomic to subgenomic RNA, recovery of cellular protein synthesis followed by reduced viral protein synthesis and inhibition of viral RNA transcription. Noncytolytic mechanisms for virus clearance result in persistence of viral RNA in the CNS. During the past granting period we have shown that both age- dependent susceptibility and noncytolytic clearance can be modeled with neuronal cell lines differentiated in vitro. In the current application we propose to determine the mechanisms of age-dependent susceptibility and of immune-mediated control of intracellular virus replication through the following specific aims: (1)To determine why mature neurons are more resistant to SV infection than immature neurons; (2)To determine what steps of virus replication are restricted in mature neurons compared to immature neurons; (3) To determine the mechanism by which IFN-? clears virus from mature neurons; and (4) To determine the mechanism by which anti-E2 antibody clears virus from mature neurons.