title: Polarity changes in the transmembrane domain core of HIV-1 Vpu inhibits its anti-tetherin activity.
abstract: Tetherin (BST-2/CD317) is an interferon-inducible antiviral protein that restricts the release of enveloped viruses from infected cells. The HIV-1 accessory protein Vpu can efficiently antagonize this restriction. In this study, we analyzed mutations of the transmembrane (TM) domain of Vpu, including deletions and substitutions, to delineate amino acids important for HIV-1 viral particle release and in interactions with tetherin. The mutants had similar subcellular localization patterns with that of wild-type Vpu and were functional with respect to CD4 downregulation. We showed that the hydrophobic binding surface for tetherin lies in the core of the Vpu TM domain. Three consecutive hydrophobic isoleucine residues in the middle region of the Vpu TM domain, I15, I16 and I17, were important for stabilizing the tetherin binding interface and determining its sensitivity to tetherin. Changing the polarity of the amino acids at these positions resulted in severe impairment of Vpu-induced tetherin targeting and antagonism. Taken together, these data reveal a model of specific hydrophobic interactions between Vpu and tetherin, which can be potentially targeted in the development of novel anti-HIV-1 drugs.
authors.affiliation: National Engineering Laboratory For AIDS Vaccine, College of Life Science, Jilin University, Changchun, Jilin Province, People's Republic of China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Lv
authors.forename: Jiawen
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Xianghui
authors.initials: X
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D002462:Cell Membrane; D015536:Down-Regulation; D005240:Feasibility Studies; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057074:Virus Release / Q000235:genetics; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D015704:CD4 Antigens; 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