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Foot-and-mouth disease virus (FMDV) rapidly causes cytopathic effects in susceptible cells.Incomplete viral clearance during the acute infection leads to persistent infection.The relationship between host gene expression and the persistent infection remains unclear.In this study,we analyzed the transcriptome profiles of BHK-21 cells acutely and persistently infected with FMDV to identify differences in gene expression.GO and KEGG enrichment analyses showed that the 8,378 differentially expressed genes were significantly enriched in categories including metabolism,biosynthesis,ribosome function,and endocytosis.In persistently infected BHK-21 cells,ribosome-and translation-related genes were significantly down-regulated.There were more differentially expressed immune-related genes during persistent infection than during acute infection.Two hundred and seventy-four genes were differentially expressed in both acutely and persistently infected BHK-21 cells.Among these genes,heat shock protein family B member 1 (Hspbl) knockdown significantly inhibited FMDV replication.Our research provides a basis for further research to understand the mechanisms of persistent FMDV infection including the genes involved in FMDV replication.