title: HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) infection is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The high incidence of AIDS-KS has been ascribed to the interaction of KSHV and HIV-1. We have previously shown that HIV-1-secreted proteins Tat and Nef regulate the KSHV life cycle and synergize with KSHV oncogenes to promote angiogenesis and tumorigenesis. Here, we examined the regulation of KSHV latency by HIV-1 viral protein R (Vpr). We found that soluble Vpr inhibits the expression of KSHV lytic transcripts and proteins, as well as viral particle production by activating NF-κB signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identified a Vpr-upregulated cellular microRNA (miRNA), miR-942-5p, that directly targeted IκBα. Suppression of miR-942-5p relieved the expression of IκBα and reduced Vpr inhibition of KSHV lytic replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV lytic replication. Our findings collectively illustrate that, by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized HIV-1 Vpr inhibits KSHV lytic replication. These results have demonstrated an essential role of Vpr in the life cycle of KSHV.
  
  
  
  Coinfection by HIV-1 promotes the aggressive growth of Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In this study, we have shown that soluble HIV-1 Vpr inhibits KSHV lytic replication by activating NF-κB signaling following internalization into PEL cells. Mechanistic studies revealed that a cellular microRNA upregulated by Vpr, miR-942-5p, directly targeted IκBα. Suppression of miR-942-5p relieved IκBα expression and reduced Vpr inhibition of KSHV replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV replication. These results indicate that by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized Vpr inhibits KSHV lytic replication. This work illustrates a molecular mechanism by which HIV-1-secreted regulatory protein Vpr regulates KSHV latency and the pathogenesis of AIDS-related malignancies.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People's Republic of China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital, Nanjing Medical University, Wuxi, People's Republic of China.
authors.forename: Chenyou
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Wan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Qin
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People's Republic of China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China clu@njmu.edu.cn.
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
mesh_terms: D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D056265:Microbial Interactions; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014775:Virus Activation; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C000594372:MIRN942 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1