Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro-survival Cytokines by Targeting the Notch/NF-κB-Signaling Axis

Abstract

HIV-1 infection significantly increases the risk of KS and PEL in KSHV-infected individuals. Our previous study has shown that HIV-1 Vpr regulates the KSHV life cycle by targeting IκBα to activate NF-κB signaling through upregulating cellular miR-942-5p. In this study, we have further found that Vpr inactivates Notch signaling to promote KSHV latency and production of pro-proliferation and -survival cytokines. Another Vpr-upregulated cellular microRNA, miR-711, participates in this process by directly targeting Notch1. As a result, Notch1 upregulation of the IκBα promoter activity is attenuated, resulting in reduced levels of IκBα transcript and protein. Overall, these results illustrate an alternative mechanism of HIV-1 Vpr regulation of KSHV latency and aberrant cytokines through the miR-711/Notch/NF-κB axis. Our novel findings further demonstrate the role of an HIV-1-secreted regulatory protein in the KSHV life cycle and KSHV-related malignancies.