title: A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2.
abstract: Human BST-2 inhibits HIV-1 replication by tethering nascent virions to the cell surface. HIV-1 codes Vpu that counteracts BST-2 by down-regulating this restriction factor from the cell surface. This important function makes Vpu a potential therapeutic target. Yet, no agents have been reported to block Vpu from antagonizing BST-2. In this study, we report a small molecule compound IMB-LA that abrogates the function of Vpu and thereby strongly suppresses HIV-1 replication by sensitizing the virus to BST-2 restriction. Further studies revealed that IMB-LA specifically inhibits Vpu-mediated degradation of BST-2 and restores the expression of BST-2 at the cell surface. Although IMB-LA does not prevent Vpu from interacting with BST-2 or β-TrCP2-containing ubiquitin E3 ligase, sorting of BST-2 into lysosomes in Vpu-expressing cells is blocked by IMB-LA. Most importantly, HIV-1 release and infection is inhibited by IMB-LA only in BST-2-expressing cells. In summary, results herein demonstrated that IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu, and impair HIV-1 replication in a BST-2 dependent manner, suggesting the feasibility of utilizing small molecule compounds to disable the antagonist function of Vpu and thereby expose HIV-1 to the restriction by BST-2.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.|Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: Zeyun
authors.initials: Z
authors.lastname: Mi
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Ding
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Union University, Beijing 100101, China.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Yu
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Shan
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Beijing Union University, Beijing 100101, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Pathogen Biology, Chinese Academy of Medical Science, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Guo
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Cen
mesh_terms: D044966:Anti-Retroviral Agents / Q000737:chemistry / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D059748:Proteolysis / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D044966:Anti-Retroviral Agents; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins