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

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 IκBα to activate the NF-κB 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-κB activity by promoting IκBα promoter activity. Our novel findings reveal that by upregulating miR-711 to target Notch1, Vpr silences Notch signaling to activate the NF-κB pathway by reducing IκBα expression, leading to inhibition of KSHV lytic replication and induction of pro-proliferation and -survival cytokines. Therefore, the miR-711/Notch/NF-κB axis is important in the pathogenesis of AIDS-related malignancies and could be an attractive therapeutic target. 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.

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…By attaching to a specific binding site on PTEN 3 UTR luciferase reporter, miR-718 decreased PTEN's tumor suppressor activity in a dose-dependent manner, thus activating the AKT/mTOR signaling pathway and therefore promoting cell proliferation and angiogenesis (Xue et al, 2014). On the same note, Yan et al have found that, in patients infected with both HIV-1 and KSHV, miR-942 and -711 were upregulated, both leading to an activation of the NF-κB signaling pathway, which, in turn, inhibited KSHV lytic replication (Yan et al, 2018). The NF-κB signaling network has previously been shown to be consistently activated during viral infections, promoting an inflammatory state as well as HIV persistence due to its ability to activate the viral transcription (Hiscott et al, 2001).…”

Pseudomonas aeruginosa Stimulates Inflammation and Enhances Kaposi’s Sarcoma Herpesvirus-Induced Cell Proliferation and Cellular Transformation through both Lipopolysaccharide and Flagellin

“…For cancers caused by infections of oncogenic viruses, HIV regulates both the replication of these viruses and the progression of their associated cancers (8). For example, HIV-encoded products Tat, Nef, and Vpr regulate KSHV replication and the functions of KSHV genes, resulting in enhanced cell migration, invasion, and angiogenesis (9)(10)(11)(12)(13)(14)(15). Moreover, long-term use of antiretroviral drugs in HIV patients is associated with an elevated risk of several cancers (16).…”

HIV-1 Tat Interacts with a Kaposi’s Sarcoma-Associated Herpesvirus Reactivation-Upregulated Antiangiogenic Long Noncoding RNA, LINC00313, and Antagonizes Its Function

“…This suggests that virus-virus interactions between KSHV and HIV are required for malignant transformation. Since the KS lesion is of endothelial cell origin and HIV does not directly infect endothelial cells, studies have focused on elucidating the circulating soluble HIV proteins that may potentiate neoplastic processes (24)(25)(26)(27)(43)(44)(45). Previous reports indicated that viral proteins secreted by HIV-infected cells may be taken up by KSHV-infected cells and consequently dysregulate the KSHV latent to lytic infection switch (39,46) and promote disease progression (24-27, 43, 45).…”