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

Coinfection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) often leads to AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The interaction between HIV and KSHV plays a pivotal role in the progression of these malignancies. We have previously demonstrated that, by upregulating miR-942-5p, HIV-1 viral protein R (Vpr) inhibits KSHV lytic replication by targeting I kappa B alpha to activate the NF-kappa B signaling (Q. Yan, C. Shen, J. Qin, W. Li, M. Hu, H. Lu, D. Qin, J. Zhu, S. J. Gao, C. Lu, J Virol 90: 8739-8753, 2016). Here, we show that Vpr inactivates Notch signaling, resulting in inhibition of KSHV lytic replication and induction of pro-proliferative and -survival cytokines, including interleukin-2 (IL-2), TIMP-1, IGF-1, and NT-4. Mechanistically, Vpr upregulates miR-711, which directly targets the Notch1 3 ' untranslated region. Suppression of miR-711 relieved Notch1 and reduced Vpr inhibition of KSHV lytic replication and Vpr induction of pro-proliferation and -survival cytokines, while overexpression of miR-711 exhibited the opposite effect. Finally, overexpression of Notch1 reduced Vpr induction of NF-kappa B activity by promoting I kappa B alpha promoter activity. Our novel findings reveal that by upregulating miR-711 to target Notch1, Vpr silences Notch signaling to activate the NF-kappa B pathway by reducing I kappa B alpha expression, leading to inhibition of KSHV lytic replication and induction of pro-proliferation and -survival cytokines. Therefore, the miR-711/Notch/NF-kappa B axis is important in the pathogenesis of AIDS-related malignancies and could be an attractive therapeutic target. IMPORTANCE 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 I kappa B alpha to activate NF-kappa B 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 I kappa B alpha promoter activity is attenuated, resulting in reduced levels of I kappa B alpha 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-kappa B axis. Our novel findings further demonstrate the role of an HIV-1-secreted regulatory protein in the KSHV life cycle and KSHV-related malignancies.