title: HIV-1 Vpr increases Env expression by preventing Env from endoplasmic reticulum-associated protein degradation (ERAD).
abstract: Vpr enhances HIV-1 replication in macrophages and dendritic cells, as well as the human CD4(+) CEM.NKR T cell line. Recently, Vpr was reported to increase HIV-1 Env expression in macrophages. Here, we report that Vpr also increases HIV-1 Env expression in dendritic cells and CEM.NKR cells. The Vpr activity depends on its N-terminal region, which was disrupted by a single A30L mutation. Env was rapidly degraded in the absence of Vpr, which was blocked by the ERAD pathway inhibitor kifunesine or the lysosome inhibitor Bafilomycin. As2O3 or PK11195, which reportedly enhances HIV-1 Env folding, also blocked the Env degradation in CEM.NKR cells. Thus, these results not only identify Env as a primary target for Vpr to boost HIV-1 replication, but also suggest that Vpr likely promotes Env folding in the ER, which is otherwise misfolded and targeted by the ERAD pathway to lysosomes for degradation.
authors.affiliation: Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin 150001, China; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin 150001, China; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Dylan A
authors.initials: DA
authors.lastname: Frabutt
authors.affiliation: Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin 150001, China; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. Electronic address: zhengyo@msu.edu.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D059748:Proteolysis; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus
keywords: Endoplasmic reticulum-associated protein degradation (ERAD); Glycoprotein; Human immunodeficiency virus (HIV); Protein degradation; Viral protein; Vpr