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Both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) establish the persistent, life-long infection primarily at the latent status, and associate with certain types of tumors, such as B cell lymphomas, especially in immuno-compromised individuals including people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that polo-like kinase 1 (PLK1) is induced by KSHV de novo infection as well as lytic switch from KSHV latency. We further demonstrated that PLK1 depletion or inhibition facilitates KSHV reactivation and promotes cell death of KSHV-infected lymphoma cells. Mechanistically, PLK1 regulates Myc that is critical to both maintenance of KSHV latency and support of cell survival, and preferentially affects the level of H3K27me3 inactive mark both globally and at certain loci of KSHV viral episomes. Furthremore, we recognized that PLK1 inhibition synergizes with STAT3 inhibition to efficiently induce KSHV reactivation. We also confirmed that PLK1 depletion or inhibition yields the similar effect on EBV lytic reactivation and cell death of EBV-infected lymphoma cells. Lastly, we noticed that PLK1 in B cells is elevated in the context of HIV infection and caused by HIV Nef protein to favor KSHV/EBV latency. Author summary: KSHV is a large double-stranded DNA virus belonging to human gamma-herpesviruses and capable of establishing the long-term persistent infection, which causes cancers under immunocompromised states, such as acquired immunodeficiency syndrome (AIDS). There are currently still no effective therapies to specifically treat KSHV-associated tumors, nor eliminate its persistent infection. In this study, we illustrated that PLK1 is upregulated by KSHV, which in return suppresses KSHV lytic infection. We further demonstrated that PLK1 is a novel host target that can be inhibited pharmacologically to benefit the viral oncolysis for promotion of KSHV lytic reactivation and elimination of KSHV-positive lymphoma cells, particularly for people living with HIV (PLWH). PLK1 inhibitors also exerted the similar effect on EBV that is the other member of human gamma-herpesvirus. [ABSTRACT FROM AUTHOR]