Effect of eIF5B silencing on KSHV-reactivated human iSLK.219 cells from 0-72 Hours reactivation

Kaposi’s Sarcoma (KS) Herpesvirus (KSHV) is the etiological agent of KS, an AIDS-defining illness. Recent studies have demonstrated that even during normoxic conditions, KSHV facilitates replication by modulating hypoxia-inducible factors (HIFs), creating a hypoxia-like environment that promotes cellular transformation. KSHV lytic viral genes are favored for protein synthesis during infection by upregulating HIF2α and utilizing the hypoxic eIF4E2 translation initiation complex in oxygen-replete conditions. This translation initiation plasticity (TRIP) links viral replication strategies to angiogenic signaling and oncogenicity. However, the molecular basis of this plasticity remains poorly understood. This study reveals that viral inhibition of eukaryotic initiation factor 2 (eIF2) induces the use of another alternative initiation factor, eIF5B, which canonically mediates delivery of initiator methionine during hypoxia. Specifically, our transcriptomic analyses reveals that the mRNA landscape in KSHV-infected cells depleted of eIF5B mirrors that of uninfected hypoxic cells, highlighted by differential gene expression of pathways involved in hypoxia and glycolysis.