Measles virus remains a substantial cause of morbidity and mortality, producing acute infection with a potential for development of viral persistence. To study the events underlying acute and persistent measles virus infection, we performed a global transcriptional analysis on murine neuroblastoma cells that were acutely or persistently infected with measles virus. In general, we found that acute infection induced significantly more gene expression changes than did persistent infection. A functional enrichment analysis to identify which host pathways were perturbed during each of these infections identified several pathways related to cholesterol biosynthesis, including cholesterol metabolic processes, hydroxymethylglutaryl-coenzyme A (CoA) reductase activity, and acetyl-CoA C-acetyltransferase activity. We also found that measles virus colocalized to lipid rafts in both acute and persistent infection models and that the majority of genes associated with cholesterol synthesis were downregulated in persistent infection relative to acute infection, suggesting a possible link with the defective viral budding in persistent infection. Further, we found that pharmacological inhibition of cholesterol synthesis resulted in the inhibition of viral budding during acute infection. In summary, persistent measles viral infection was associated with decreased cholesterol synthesis, a lower abundance of cholesterol and lipid rafts in the cell membrane, and inhibition of giant-cell formation and release of viral progeny.Measles virus (MV) remains a significant health burden, claiming 450,000 lives worldwide every year, and most of the deaths occur in children (35). MV is the etiological agent of both acute measles infection and subacute sclerosing panencephalitis (SSPE), a rare and devastating persistent infection of the central nervous system (7,8,12). MV is typically highly cytolytic, resulting in an acute infection that confers lifelong immunity. The reasons and underlying mechanisms of transformation into a persistent infection in some individuals remain unknown, and the pathological implications of such an infection are controversial.Although no mechanism for the transformation from acute to persistent infection has been established, partial explanations have been proposed. Defective measles matrix (M) protein has been recovered in some SSPE cases and was suggested as a possible underlying mechanism for persistence (11,15,20). Our previous research also demonstrated that there is significantly less viral budding in persistent versus acute MV infection of murine neuroblastoma cell lines and that this is not due to decreased viral protein synthesis, which is unimpaired (22,25). Viral budding in MV infection involves the incorporation of envelope proteins into the host cell membrane (5). This has been recently shown to occur in lipid rafts-cholesterol-rich domains in the cellular membrane (17,19,21,33).In this study, we used microarray analysis to compare gene expression during acute and persistent infection with MV and to id...