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KSHV is associated with number of human malignancies.Increasing evidences suggest that lytic cycle of the virus plays important roles in virus-mediated oncogenesis.A comprehensive understanding of KSHV lytic cycle will lead to novel strategies to treat KSHV-associated diseases.Here we report that APE-1 protein is critically required for KSHV reactivation and inhibitors of APE-1 effectively inhibit lytic replication of the virus.