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The antiviral activity of TDRD7 was dependent on its ability to inhibit virus-activated AMPK. In summary, our results indicate that the newly identified viral restriction factor TDRD7 inhibits AMPK and thereby blocks HSV-1 replication independently of the autophagy pathway. These findings suggest that AMPK inhibition represents a potential strategy to manage HSV-1 infections. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Myosin II is the main force-generating motor during muscle contraction.