ABSTRACTAn outbreak of the novel coronavirus SARS‐CoV‐2, the causative agent of COVID‐19 pandemic, has resulted in over 7 million confirmed deaths. In addition to severe respiratory and systematic symptoms, several comorbidities increase the risk of fatal outcomes. Therefore, it is essential to investigate the impact of COVID‐19 on pre‐existing conditions in patients, such as cancer and other infectious diseases. Recent clinical studies have reported the reactivation of human herpesviruses, including Kaposi's sarcoma‐associated herpesvirus (KSHV), in severe COVID‐19 patients or vaccinated individuals. To support these clinical observations, we established a KSHV/SARS‐CoV‐2 co‐infection system in A549‐hACE2 cells. Our findings indicate that co‐infection with live SARS‐CoV‐2 sharply induces KSHV lytic reactivation. Transcriptomic analysis revealed significant changes in global cellular gene expression in KSHV‐infected A549‐hACE2 cells, both with and without SARS‐CoV‐2 co‐infection. These data provide a molecular basis for understanding whether patients with pre‐existing oncogenic herpesvirus infections are at increased risk for more severe COVID‐19 or for developing virus‐associated cancers even after full recovery from COVID‐19.
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