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Failure of Measles Virus to Activate Nuclear Factor-B in Neuronal Cells: Implications on the Immune Response to Viral Infections in the Central Nervous System¹

Department of Neurology, University of Maryland at Baltimore, Baltimore, MD 21201; and Department of Veterans Affairs, Baltimore, MD 21201

Neurons are postmitotic cells that foster virus persistence. These cells lack the HLA class I molecules required for clearance of infected cells. Previously, we showed that HLA class I is induced by measles virus (MV) on glial cells, which is primarily mediated by IFN-ß. In contrast, MV was unable to induce HLA class I or IFN-ß in neuronal cells. This failure was associated with lack of NF-B binding to the positive regulatory domain II element of the IFN-ß promoter, which is essential for virus-induced IFN-ß gene activity. In this study, we demonstrate that the failure to activate NF-B in neuronal cells is due to the inability of MV to induce phosphorylation and degradation of IB, the inhibitor of NF-B. In contrast, TNF- induced degradation of IB in the neuronal cells, suggesting that failure to induce IB degradation is likely due to a defect in virus-mediated signaling rather than to a defect involving neuronal IB. Like MV, mumps virus and dsRNA failed to induce IB degradation in the neuronal cells, suggesting that this defect may be specific to viruses. Autophosphorylation of the dsRNA-dependent protein kinase, a kinase possibly involved in virus-mediated IB phosphorylation, was intact in both cell types. The failure of virus to induce IB phosphorylation and consequently to activate NF-B in neuronal cells could explain the repression of IFN-ß and class I gene expression in virus-infected cells. These findings provide a potential mechanism for the ability of virus to persist in neurons and to escape immune surveillance.

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