Inhibition of Polo-like kinase 1 (PLK1) to facilitate the reactivation and elimination of latent gamma-herpesviruses.

Both Kaposis sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) can establish the persistent, life-long infection primarily at the latent status, and contribute to certain types of tumors, including B cell lymphomas, especially in immuno-compromised individuals, such as 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 expression of Polo-like kinase 1 (PLK1) in B cells is elevated in the context of HIV infection and by HIV Nef protein. We further demonstrated that PLK1 depletion or inhibition can promote KSHV reactivation and cell death of KSHV-reactivated tumor cells. Mechanistically, PLK1 regulates Myc protein that is critical for both maintenance of KSHV latency and support of cell survival, and affects the level of H3K27me3 suppressive mark both globally and at certain loci of KSHV viral episomes. Lastly, we recognized that PLK1 inhibition can synergize with STAT3 inhibition to induce efficient KSHV reactivation. PLK1 depletion or inhibition yielded the similar effect on promoting EBV reactivation and cell death of EBV-reactivated tumor cells. Our findings illustrated that PLK1 is a novel host target that can be inhibited to benefit the viral oncolysis to eliminate KSHV/EBV-infected tumor cells.