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HIV Interactions with Host Cell Proteins pp 27–45Cite as

Interactions of Viral protein U (Vpu) with Cellular Factors

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 339))

Abstract

Viral protein U (Vpu) is encoded by one of several accessory genes of HIV-1. Like the accessory gene products Vif and Vpr, Vpu targets host proteins such as CD4 for degradation via the recruitment of cellular multi-subunit ubiquitin ligases. Vpu also forms ion channels in cellular membranes. Through one or both of these attributes, Vpu antagonizes host cell factors that restrict the release of progeny virions from infected cells. A key target of Vpu has recently been identified as the interferon-induced transmembrane protein BST-2/CD317 (tetherin), which restricts viral replication by retaining nascent virions on the cell surface. The counteraction of this host defense allows Vpu to be considered an antagonist of the innate immune response to viral infection.

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References

  • Aiken C, Konner J, Landau NR, Lenburg M, Trono D (1994) Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76:853–864

    Article  PubMed  CAS  Google Scholar 

  • Akari H, Bour S, Kao S, Adachi A, Strebel K (2001) The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors. J Exp Med 194:1299–1311

    Article  PubMed  CAS  Google Scholar 

  • Bartee E, McCormack A, Fruh K (2006) Quantitative membrane proteomics reveals new cellular targets of viral immune modulators. PLoS. Pathog. 2:e107

    Google Scholar 

  • Benson RE, Sanfridson A, Ottinger JS, Doyle C, Cullen BR (1993) Downregulation of cell-surface CD4 expression by simian immunodeficiency virus nef prevents viral super infection. J Exp Med 177:1561–1566

    Article  PubMed  CAS  Google Scholar 

  • Besnard-Guerin C, Belaidouni N, Lassot I, Segeral E, Jobart A, Marchal C, Benarous R (2004) HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates. J Biol Chem 279:788–795

    Article  PubMed  CAS  Google Scholar 

  • Blasius AL, Giurisato E, Cella M, Schreiber RD, Shaw AS, Colonna M (2006) Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation. J Immunol 177:3260–3265

    PubMed  CAS  Google Scholar 

  • Bour S, Perrin C, Akari H, Strebel K (2001) The human immunodeficiency virus type 1 Vpu protein inhibits NF-kappa B activation by interfering with beta TrCP-mediated degradation of Ikappa B. J Biol Chem 276:15920–15928

    Article  PubMed  CAS  Google Scholar 

  • Bour S, Schubert U, Peden K, Strebel K (1996) The envelope glycoprotein of human immunodeficiency virus type 2 enhances viral particle release: a Vpu-like factor? J Virol 70:820–829

    PubMed  CAS  Google Scholar 

  • Bour S, Schubert U, Strebel K (1995) The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation. J Virol 69:1510–1520

    PubMed  CAS  Google Scholar 

  • Bram RJ, Crabtree GR (1994) Calcium signalling in T cells stimulated by a cyclophilin B-binding protein. Nature 371:355–358

    Article  PubMed  CAS  Google Scholar 

  • Callahan MA, Handley MA, Lee YH, Talbot KJ, Harper JW, Panganiban AT (1998) Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family. J Virol 72:5189–5197

    PubMed  CAS  Google Scholar 

  • Cohen EA, Terwilliger EF, Sodroski JG, Haseltine WA (1988) Identification of a protein encoded by the vpu gene of HIV-1. Nature 334:532–534

    Article  PubMed  CAS  Google Scholar 

  • Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D (1998) HIV-1 nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391:397–400

    Article  PubMed  CAS  Google Scholar 

  • Cziepluch C, Kordes E, Poirey R, Grewenig A, Rommelaere J, Jauniaux JC (1998) Identification of a novel cellular TPR-containing protein, SGT, that interacts with the nonstructural protein NS1 of parvovirus H-1. J Virol 72:4149–4156

    PubMed  CAS  Google Scholar 

  • Dutta S, Tan YJ (2008) Structural and Functional Characterization of Human SGT and Its Interaction with Vpu of the Human Immunodeficiency Virus Type 1(,). Biochemistry 47:10123–10131

    Article  PubMed  CAS  Google Scholar 

  • Evrard-Todeschi N, Gharbi-Benarous J, Bertho G, Coadou G, Megy S, Benarous R, Girault JP (2006) NMR studies for identifying phosphopeptide ligands of the HIV-1 protein Vpu binding to the F-box protein beta-TrCP. Peptides 27:194–210

    Article  PubMed  CAS  Google Scholar 

  • Ewart GD, Mills K, Cox GB, Gage PW (2002) Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by HIV-1 protein Vpu. Eur Biophys J 31:26–35

    Article  PubMed  CAS  Google Scholar 

  • Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH (1999) Origins of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397:436–441

    Article  PubMed  CAS  Google Scholar 

  • Geraghty RJ, Talbot KJ, Callahan M, Harper W, Panganiban AT (1994) Cell type-dependence for Vpu function. J Med Primatol 23:146–150

    PubMed  CAS  Google Scholar 

  • Gonzalez ME, Carrasco L (2003) Viroporins. FEBS Lett 552:28–34

    Article  PubMed  CAS  Google Scholar 

  • Gottlinger HG, Dorfman T, Cohen EA, Haseltine WA (1993) Vpu protein of human immunodeficiency virus type 1 enhances the release of capsids produced by gag gene constructs of widely divergent retroviruses. Proc Natl Acad Sci USA 90:7381–7385

    Article  PubMed  CAS  Google Scholar 

  • Henderson WW, Ruhl R, Lewis P, Bentley M, Nelson JA, Moses AV (2004) Human immunodeficiency virus (HIV) type 1 Vpu induces the expression of CD40 in endothelial cells and regulates HIV-induced adhesion of B-lymphoma cells. J Virol 78:4408–4420

    Article  PubMed  CAS  Google Scholar 

  • Hiltbold EM, Roche PA (2002) Trafficking of MHC class II molecules in the late secretory pathway. Curr Opin Immunol 14:30–35

    Article  PubMed  CAS  Google Scholar 

  • Holloway MP, Bram RJ (1998) Co-localization of calcium-modulating cyclophilin ligand with intracellular calcium pools. J Biol Chem 273:16346–16350

    Article  PubMed  CAS  Google Scholar 

  • Hout DR, Gomez LM, Pacyniak E, Miller JM, Hill MS, Stephens EB (2006) A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian-human immunodeficiency virus (SHIV(KU-1bMC33)) susceptible to rimantadine. Virology 348(2):449–461

    Article  PubMed  CAS  Google Scholar 

  • Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J (2007) Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci USA 104:11778–11783

    Article  PubMed  CAS  Google Scholar 

  • Hsu K, Seharaseyon J, Dong P, Bour S, Marban E (2004) Mutual functional destruction of HIV-1 Vpu and host TASK-1 channel. Mol Cell 14:259–267

    Article  PubMed  CAS  Google Scholar 

  • Hussain A, Wesley C, Khalid M, Chaudhry A, Jameel S (2008) Human immunodeficiency virus type 1 Vpu protein interacts with CD74 and modulates major histocompatibility complex class II presentation. J Virol 82:893–902

    Article  PubMed  CAS  Google Scholar 

  • Kerkau T, Bacik I, Bennink JR, Yewdell JW, Hunig T, Schimpl A, Schubert U (1997) The human immunodeficiency virus type 1 (HIV-1) Vpu protein interferes with an early step in the biosynthesis of major histocompatibility complex (MHC) class I molecules. J Exp Med 185:1295–1305

    Article  PubMed  CAS  Google Scholar 

  • Klimkait T, Strebel K, Hoggan MD, Martin MA, Orenstein JM (1990) The human immunodeficiency virus type 1-specific protein vpu is required for efficient virus maturation and release. J Virol 64(2):621–629

    PubMed  CAS  Google Scholar 

  • Kupzig S, Korolchuk V, Rollason R, Sugden A, Wilde A, Banting G (2003) Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic 4:694–709

    Article  PubMed  CAS  Google Scholar 

  • Lama J, Mangasarian A, Trono D (1999) Cell-surface expresion of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr Biol 9:622–631

    Article  PubMed  CAS  Google Scholar 

  • Levesque K, Zhao YS, Cohen EA (2003) Vpu exerts a positive effect on HIV-1 infectivity by down-modulating CD4 receptor molecules at the surface of HIV-1-producing cells. J Biol Chem 278:28346–28353

    Article  PubMed  CAS  Google Scholar 

  • Lopez CF, Montal M, Blasie JK, Klein ML, Moore PB (2002) Molecular dynamics investigation of membrane-bound bundles of the channel-forming transmembrane domain of viral protein U from the human immunodeficiency virus HIV-1. Biophys J 83:1259–1267

    Article  PubMed  CAS  Google Scholar 

  • Malim MH, Emerman M (2008) HIV-1 accessory proteins–ensuring viral survival in a hostile environment. Cell Host Microbe 3:388–398

    Article  PubMed  CAS  Google Scholar 

  • Margottin F, Benichou S, Durand H, Richard V, Liu LX, Gomas E, Benarous R (1996) Interaction between the cytoplasmic domains of HIV-1 Vpu and CD4: role of Vpu residues involved in CD4 interaction and in vitro CD4 degradation. Virology 223:381–386

    Article  PubMed  CAS  Google Scholar 

  • Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R (1998) A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1:565–574

    Article  PubMed  CAS  Google Scholar 

  • McCormick PJ, Martina JA, Bonifacino JS (2005) Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments. Proc Natl Acad Sci USA 102:7910–7915

    Article  PubMed  CAS  Google Scholar 

  • Neil SJ, Eastman SW, Jouvenet N, Bieniasz PD (2006) HIV-1 Vpu promotes release and prevents endocytosis of nascent retrovirus particles from the plasma membrane. PLoS Pathog 2:e39

    Article  PubMed  Google Scholar 

  • Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD (2007) An interferon-alpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe 2:193–203

    Article  PubMed  CAS  Google Scholar 

  • Neil SJ, Zang T, Bieniasz PD (2008) Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451:425–430

    Article  PubMed  CAS  Google Scholar 

  • Ohtomo T, Sugamata Y, Ozaki Y, Ono K, Yoshimura Y, Kawai S, Koishihara Y, Ozaki S, Kosaka M, Hirano T, Tsuchiya M (1999) Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. Biochem Biophys Res Commun 258:583–591

    Article  PubMed  CAS  Google Scholar 

  • Pacyniak E, Gomez ML, Gomez LM, Mulcahy ER, Jackson M, Hout DR, Wisdom BJ, Stephens EB (2005) Identification of a region within the cytoplasmic domain of the subtype B Vpu protein of human immunodeficiency virus type 1 (HIV-1) that is responsible for retention in the Golgi complex and its absence in the Vpu protein from a subtype C. AIDS Res Hum Retroviruses 21:379–394

    Article  PubMed  CAS  Google Scholar 

  • Park SH, Mrse AA, Nevzorov AA, Mesleh MF, Oblatt-Montal M, Montal M, Opella SJ (2003) Three-dimensional structure of the channel-forming trans-membrane domain of virus protein “u” (Vpu) from HIV-1. J Mol Biol 333:409–424

    Article  PubMed  CAS  Google Scholar 

  • Ross TM, Oran AE, Cullen BR (1999) Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral nef protein. Curr. Biol. 9:613–621

    Article  PubMed  CAS  Google Scholar 

  • Ruiz A, Hill MS, Schmitt K, Guatelli J, Stephens EB (2008) Requirements of the membrane proximal tyrosine and dileucine-based sorting signals for efficient transport of the subtype C Vpu protein to the plasma membrane and in virus release. Virology 378:58–68

    Article  PubMed  CAS  Google Scholar 

  • Sakaguchi T, Leser GP, Lamb RA (1996) The ion channel activity of the influenza virus M2 protein affects transport through the Golgi apparatus. J Cell Biol 133:733–747

    Article  PubMed  CAS  Google Scholar 

  • Sakai H, Tokunaga K, Kawamura M, Adachi A (1995) Function of human immunodeficiency virus type 1 Vpu protein in various cell types. J Gen Virol 76(Pt. 11):2717–2722

    Article  PubMed  CAS  Google Scholar 

  • Schubert U, Anton LC, Bacik I, Cox JH, Bour S, Bennink JR, Orlowski M, Strebel K, Yewdell JW (1998) CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. J Virol 72:2280–2288

    PubMed  CAS  Google Scholar 

  • Schubert U, Bour S, Ferrer-Montiel AV, Montal M, Maldarell F, Strebel K (1996a) The two biological activities of human immunodeficiency virus type 1 Vpu protein involve two separable structural domains. J Virol 70:809–819

    PubMed  CAS  Google Scholar 

  • Schubert U, Clouse KA, Strebel K (1995) Augmentation of virus secretion by the human immunodeficiency virus type 1 Vpu protein is cell type independent and occurs in cultured human primary macrophages and lymphocytes. J Virol 69:7699–7711

    PubMed  CAS  Google Scholar 

  • Schubert U, Ferrer-Montiel AV, Oblatt-Montal M, Henklein P, Strebel K, Montal M (1996b) Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1-infected cells. FEBS Lett 398:12–18

    Article  PubMed  CAS  Google Scholar 

  • Schwartz S, Felber BK, Fenyo E-M, Pavlakis GN (1990) Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs. J Virol 64:5448–5456

    PubMed  CAS  Google Scholar 

  • Strebel K, Klimkait T, Martin MA (1988) A novel gene of HIV-1, vpu, and its 16-kilodalton product. Science 241:1221–1223

    Article  PubMed  CAS  Google Scholar 

  • Terwilliger EF, Cohen EA, Lu YC, Sodroski JG, Haseltine WA (1989) Functional role of human immunodeficiency virus type 1 vpu. Proc Natl Acad Sci USA 86:5163–5167

    Article  PubMed  CAS  Google Scholar 

  • Tran DD, Edgar CE, Heckman KL, Sutor SL, Huntoon CJ, van DJ, McKean DL, Bram RJ (2005) CAML is a p56Lck-interacting protein that is required for thymocyte development. Immunity 23:139–152

    Article  PubMed  CAS  Google Scholar 

  • Tran DD, Russell HR, Sutor SL, van DJ, Bram RJ (2003) CAML is required for efficient EGF receptor recycling. Dev Cell 5:245–256

    Article  PubMed  CAS  Google Scholar 

  • Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, Stephens EB, Guatelli J (2008) The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3:245–252

    Article  PubMed  Google Scholar 

  • Van Damme N, Guatelli J (2007) HIV-1 Vpu inhibits accumulation of the envelope glycoprotein within clathrin-coated, Gag-containing endosomes. Cell Microbiol 10(5):1040–1057

    Article  PubMed  Google Scholar 

  • Varthakavi V, Heimann-Nichols E, Smith RM, Sun Y, Bram RJ, Ali S, Rose J, Ding L, Spearman P (2008) Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu. Nat Med 14:641–647

    Article  PubMed  CAS  Google Scholar 

  • Varthakavi V, Smith RM, Bour SP, Strebel K, Spearman P (2003) Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production. Proc Natl Acad Sci USA 100:15154–15159

    Article  PubMed  CAS  Google Scholar 

  • Varthakavi V, Smith RM, Martin KL, Derdowski A, Lapierre LA, Goldenring JR, Spearman P (2006) The pericentriolar recycling endosome plays a key role in Vpu-mediated enhancement of HIV-1 particle release. Traffic 7:298–307

    Article  PubMed  CAS  Google Scholar 

  • Vidal-Laliena M, Romero X, March S, Requena V, Petriz J, Engel P (2005) Characterization of antibodies submitted to the B cell section of the 8th Human Leukocyte Differentiation Antigens Workshop by flow cytometry and immunohistochemistry. Cell Immunol 236:6–16

    Article  PubMed  CAS  Google Scholar 

  • Vincent MJ, Abdul Jabbar M (1995) The human immunodeficiency virus type 1 Vpu protein: a potential regulator of proteolysis and protein transport in the mammalian secretory pathway. Virology 213:639–649

    Article  PubMed  CAS  Google Scholar 

  • von Bulow GU, Russell H, Copeland NG, Gilbert DJ, Jenkins NA, Bram RJ (2000) Molecular cloning and functional characterization of murine transmembrane activator and CAML interactor (TACI) with chromosomal localization in human and mouse. Mamm Genome 11:628–632

    Article  Google Scholar 

  • Willbold D, Hoffmann S, Rosch P (1997) Secondary structure and tertiary fold of the human immunodeficiency virus protein U (Vpu) cytoplasmic domain in solution. Eur J Biochem 245:581–588

    Article  PubMed  CAS  Google Scholar 

  • Willey RL, Maldarelli F, Martin MA, Strebel K (1992) Human immunodeficiency virus type 1 Vpu protein regulates the formation of intracellular gp160-CD4 complexes. J Virol 66:226–234

    PubMed  CAS  Google Scholar 

  • Wittlich M, Koenig BW, Hoffmann S, Willbold D (2007) Structural characterization of the transmembrane and cytoplasmic domains of human CD4. Biochim Biophys Acta 1768:2949–2960

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP (2003) Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell 11:1445–1456

    Article  PubMed  CAS  Google Scholar 

  • Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, Yu XF (2003) Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 302:1056–1060

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

I thank Fabian Filipp, Richard Mitchell, and Mark Skasko for review of the manuscript, and the members of my laboratory for their hard work and insights. This work was supported by grants AI038201, AI076040, and AI081668 from the National Institutes of Health, USA.

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  1. Department of Medicine, University of California-San Diego and the San Diego Department of Veterans Affairs Healthcare System, 9500 Gilman Drive, La Jolla, CA, 92093-0679, USA

    John C. Guatelli

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  1. John C. Guatelli
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Correspondence to John C. Guatelli .

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Editors and Affiliations

  1. School of Medicine, Dept. Pediatrics, Emory University, Uppergate Drive NE., 2015, Atlanta, 30322, Georgia, USA

    Paul Spearman

  2. HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, Maryland, USA

    Eric O. Freed

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Guatelli, J.C. (2009). Interactions of Viral protein U (Vpu) with Cellular Factors. In: Spearman, P., Freed, E. (eds) HIV Interactions with Host Cell Proteins. Current Topics in Microbiology and Immunology, vol 339. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-02175-6_2

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