The Human Immunodeficiency Virus Type 1 Vpu Protein: Roles in Virus Release and CD4 Downregulation

  • M. Abdul Jabbar
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 193)


Human immunodeficiency virus type 1 (HIV-1) is a complex retrovirus that encodes a number of novel regulatory proteins (Tat, Rev, Nef, Vpr, Vif and Vpu) in addition to the canonical structural proteins (Gag, Pol, and Env) that are common to all retroviruses. HIV-1 is the causative agent of the acquired immunodeficiency syndrome (AIDS). The complexity of HIV genomes reveals the complex nature of host-virus interactions in AIDS pathogenesis (Levy 1993; Weiss 1993). Some of the HIV-1 proteins are involved in the regulation of gene expression in virus-infected cells. For example, the Tat and Rev proteins are essential for HIV replication in tissue culture (Cullen 1992). These proteins have been shown to exert their effects through specific interactions with viral RNA: trans-acting response element (TAR) in the case of Tat and Rev response element (RRE) in the case of Rev. The mechanism of action of these proteins will not be considered in this review, as they will be discussed elsewhere in this volume.


Human Immunodeficiency Virus Human Immunodeficiency Virus Type Cytoplasmic Domain Envelope Glycoprotein Virus Release 
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  1. Acres RB, Conlon PJ, Mochizuki DY, Gallis B (1986) Rapid phosphorylation and modulation of the T4 antigen on cloned helper T cells induced by phorphol myristate acetate or antigen. J Biol Chem 261: 16210–16214PubMedGoogle Scholar
  2. Balliet JW, Kolson DL, Eiger G, Kim FM, McCann KA, Srinivasan A, Collman R (1994) Distinct effects of primary macrophages and lymphocytes of the human immunodeficiency virus type I accessory genes vpr, vpu, nef: mutational analysis of a primary HIV-I isolate. Virology 200: 623–631PubMedCrossRefGoogle Scholar
  3. Bonifacino JS, Cosson P, Shah N, Klausner RD (1991) Role of potentially charged transmembrane residues in targeting proteins for retention and degradation within the endoplasmic reticulum EMBO J 10: 2783–2793PubMedGoogle Scholar
  4. Bour S, Bourlerice F, Wainberg MA (1991) Inhibition of gp160 and CD4 maturation in U937 cells after both defective and productive infections by human immunodeficiency virus type 1. J Virol 65: 6387–6396PubMedGoogle Scholar
  5. Bryant M, Ratner L (1990) Myristylation-dependent replication and assembly of human immunodeficiency virus type I. Proc Natl Acad Sci USA 87: 523–527PubMedCrossRefGoogle Scholar
  6. Buonocore L, Rose JK (1990) Prevention of HIV-1 glycoprotein transport by soluble CD4 retained in the endoplasmic reticulum. Nature 345: 625–628PubMedCrossRefGoogle Scholar
  7. Buonocore L, Turi TG, Crise B, Rose JK (1994) Stimulation of heterologous protein degradation by the Vpu Protein of HIV-1 requires the transmembrane and cytoplasmic domains of CD4. Virology 204: 482–486PubMedCrossRefGoogle Scholar
  8. Chen M-T, Malderelli F, Karczewski MK, Willey RL, Strebel K (1993) Human immunodeficiency virus type 1 Vpu protein induces degradation of CD4 in vitro: the cytoplasmic domain of CD4 contributes to vpu sensitivity. J Virol 67: 3877–3884PubMedGoogle Scholar
  9. Cohen EA, Terwilliger EF, Sodroski JG, Haseltine WA (1988) Identification of a protein encoded by the vpu gene of HIV-1. Nature 334: 532–534PubMedCrossRefGoogle Scholar
  10. Crise B, Buonocore L, Rose JK (1990) CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus envelope glycoprotein precursor. J Virol 64: 5585–5593PubMedGoogle Scholar
  11. Cullen BR (1992) Mechanism of actions of regulatory proteins encoded by complex retroviruses. Microbiol Rev 56: 375–394PubMedGoogle Scholar
  12. Dalgleish AG, Beverley PCL, Clapham PR, Crawford DH, Greaves MF, Weiss RA (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312: 763–768PubMedCrossRefGoogle Scholar
  13. Doms RW, Lamb RA, Rose JK, Helenius A (1993) Folding and assembly of viral membrane proteins. virology 193: 545–562PubMedCrossRefGoogle Scholar
  14. Geraghty RJ, Panganiban AT (1993) Human immunodeficiency virus type 1 Vpu has a CD4- and an envelope glycoprotein-independent function. J Virol 67: 4190–4194PubMedGoogle Scholar
  15. Gething M-J, Sambrook J (1992) Protein folding in the cell. Nature 355: 33–45PubMedCrossRefGoogle Scholar
  16. Gottlinger HG, Sodroski JG, Haseltine WA (1989) Role of capsid precursor processing and myristylation in morphogenesis and infecitvity of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 86: 5781–5785PubMedCrossRefGoogle Scholar
  17. Gottlinger HG, Dorfman T, Sodroski JG, Haseltine WA (1991) Effects of mutations affecting the p6 gag protein on human immunodeficiency virus particle release. Proc Natl Acad Sci USA 88: 3195–3199PubMedCrossRefGoogle Scholar
  18. 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: 7381–7385PubMedCrossRefGoogle Scholar
  19. Haseltine WA (1991) Molecular biology of the human immunodeficiency virus type 1. FASEB J 5: 2349–2360PubMedGoogle Scholar
  20. Holsinger LJ, Nichani D, Pinto LH, Lamb RA (1994) Influenza A virus M2 ion channel protein: a structure-functional analysis. J Virol 68: 1551–1563PubMedGoogle Scholar
  21. Hunter E (1994) Molecular interactions in the assembly of HIV and other retroviruses. Semin Virol 5: 71–83CrossRefGoogle Scholar
  22. Hurtley SM, Helenius A (1987) Protein oligomerization in the endoplasmic reticulum. Ann Rev Cell Biol 5: 277–307CrossRefGoogle Scholar
  23. Jabbar MA, Nayak DP (1990) Intracellular interaction of human immunodeficiency virus type 1 (ARV-2) envelope glycoprotein gp160 with CD4 blocks the movement and maturation of CD4 to the plasma membrane. J Virol 64: 6297–6304PubMedGoogle Scholar
  24. Kawamura I, Koga Y, Oh-Hori N, Onodera K, Kimura G, Nomoto K (1989) Depletion of the surface CD4 molecules by the envelope protein of human immunodeficiency virus expressed in a human CD4+ monocytoid cell line. J Virol 63: 3748–3754PubMedGoogle Scholar
  25. Klatzman D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman J-C, Montagnier L (1984) T-lymphocyte T4 molecule behaves as the receptor molecule for retrovirus LAV. Nature 312: 767–768CrossRefGoogle Scholar
  26. Klausner RD, Sitia R (1990) Protein degradation in the endoplasmic reticulum. Cell 62: 611–614PubMedCrossRefGoogle Scholar
  27. Klausner RD, Donaldson JG, Lippincott-Schwartz J (1992) Brefeldin A: insight into the control of membrane traffic and organelle structure. J Cell Biol 116: 1071–1080PubMedCrossRefGoogle Scholar
  28. 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: 621–629PubMedGoogle Scholar
  29. Lenburg ME, Landau NR (1993) Vpu-induced degradation of CD4: requirement for specific amino acid residues in the cytoplasmic domain of CD4. J Virol 67: 7238–7245PubMedGoogle Scholar
  30. Levy JA (1993) Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 57: 183–289PubMedGoogle Scholar
  31. Lu Y-L, Spearman P, Ratner L (1993) Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol 67: 6542–6550PubMedGoogle Scholar
  32. Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R (1986) The T4 gene encodes the AIDS virus receptor molecule and is expressed in immune system and the brain. Cell 47: 333–348PubMedCrossRefGoogle Scholar
  33. Maddon PJ, Molineaux SM, Maddon DE, Zimmerman KA, Godfrey M, Alt FW, Chess L, Axel R (1987) Structure and expression of the human and mouse T4 genes. Proc Natl Acad Sci USA 84: 9155–9159PubMedCrossRefGoogle Scholar
  34. Maldarelli F, Chen M-Y, Willey RL, Strebel K (1993) Human immunodeficiency virus type 1 vpu protein is an oligomeric type 1 integral membrane protein. J Virol 67: 5056–5061PubMedGoogle Scholar
  35. McDougal JC, Kennedy MS, Sligh JM, Cort SP, Mawle A, Nicholson JKA (1986) Binding of HTLV-III/LAV to T4+ T-cells by a complex of the 110K viral protein and the T4 molecules. Science 231: 382–385PubMedCrossRefGoogle Scholar
  36. Paxton W, Connor RI, Landau NR (1993) Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirements for the p6 region of gag and mutational analysis. J Virol 67: 7229–7237PubMedGoogle Scholar
  37. Pelham HRB, (1991) Multiple targets for brefeldin-A. Cell 67: 449–451PubMedCrossRefGoogle Scholar
  38. Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel activity. Cell 69: 517–528PubMedCrossRefGoogle Scholar
  39. Raja NU, Vincent MJ, Jabbar MA, (1993) Anlaysis of endoproteolytic cleavegae and intracellular transport of human immunodeficiency virus type 1 envelope glycoproteins using mutant CD4 molecules bearing the transmembrane ER retention signal. J Gen Virol 74: 2085–2097PubMedCrossRefGoogle Scholar
  40. Raja NU, Vincent MJ, Jabbar MA (1994) Vpu mediated proteolysis of gp160/CD4 chimeric envelope glycoproteins in the endoplasmic reticulum: requirement of both the anchor and cytoplasmic domains of CD4 Virology 204: 357–366PubMedCrossRefGoogle Scholar
  41. Sanchez-Pescador R, Power D, Barr PJ, Steimer KS, Stempien M, Brown-Shimer SL, Gee WW, Renard A, Randolph A, Levy JA, Dina D, Luciw PA (1985) Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science 227: 484–492PubMedCrossRefGoogle Scholar
  42. Schubert U, Strebel K (1994) Differential activities of the human immunodeficiency virus-encoded Vpu protein are regulated by phosphorylation and occurs in different compartments. J Virol 68: 2260–2271PubMedGoogle Scholar
  43. Schubert U, Henklein P, Boldyreff B, Wingender E, Strebel K, Porstmann T (1994) The human immunodeficiency virus type 1 encoded Vpu protein is phosphorylayed by casein kinase-2 (CK-2) at positions ser52 and ser56 within a predicted a-helix-tum-a-helix-motif. J Mol Biol 236: 16–25PubMedCrossRefGoogle Scholar
  44. 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: 5448–5456PubMedGoogle Scholar
  45. Shin J, Lee S, Strominger JL (1993) Translocation of TCRα chains into the lumen of the endoplasmic reticulum and their degradation. Science 259: 1901–1904PubMedCrossRefGoogle Scholar
  46. Shin J, Doyle C, Yang Z, Kappes D, Strominger JL (1990) Structural features of the cytoplasmic region of CD4 required for intemalization. EMBO J 9: 425–434PubMedGoogle Scholar
  47. Shin J, Dunbrack RL, Lee S, Strominger JL (1991) Phosphorylation-dependent down-modulation of CD4 requires a specific structure within the cytoplasmic domain of CD4. J Biol Chem 266: 10658–10665PubMedGoogle Scholar
  48. Strebel K, Klimkait T, Martin MA (1988) A novel gene of HIV-1, vpu, and its 16-kilodalton product. Science 241: 1221–1223PubMedCrossRefGoogle Scholar
  49. Strebel K, Klimkait T, Maldarelli F, Martin MA (1989) Molecular and Biochemical analyses of human immunodeficiency virus type 1 vpu protein. J Virol 63: 3784–3791PubMedGoogle Scholar
  50. Takeuchi K, Lamb RA (1994) Influenza virus M2 protein ion channel activity stabilizes the native form of fowl plague hemagglutinin during intracellular transport. J Virol 68: 911–919PubMedGoogle Scholar
  51. Terwilliger EF, Cohen EA, Lu Y, Sodroski JG, Haseltine WA (1989) Functional role of human immunodeficiency virus type 1 vpu. Proc Natl Acad Sci USA 86: 5163–5167PubMedCrossRefGoogle Scholar
  52. Vincent MJ, Raja NU, Jabbar MA (1993) The human immunodeficiency virus type 1 vpu protein induces degradation of chimeric envelope glycoproteins bearing the cytoplasmic and anchor domains of CD4: role of cytoplasmic domain in Vpu-induced degradation in the endoplasmic reticulum. J Virol 67: 5538–5549PubMedGoogle Scholar
  53. von Heijne G (1988) Transcending the impenetrable: how proteins come to terms with membranes. Biochim Biophys Acta 189: 239–242Google Scholar
  54. von Schewedler U, Song J, Aiken C, Trono D (1993) vif is crucial for human immunodeficiency virus type 1 proviral DNA synthesis in infected cells. J Virol 67: 4945–4955Google Scholar
  55. Weiss A, Littman DR (1994) Signal transduction by lymphocyte antigen receptors. Cell 76: 263–274PubMedCrossRefGoogle Scholar
  56. Weiss RA (1993) How does HIV cause AIDS? Science 260: 1273–1279PubMedCrossRefGoogle Scholar
  57. Willey RL, Bonifacino JS, Potts BJ, Martin MA, Klausner RD (1988) Biosynthesis, cleavage, and degradation of the human immunodeficiency virus 1 envelope glycoprotein gp160. Proc Natl Acad Sci USA 85: 9580–9584PubMedCrossRefGoogle Scholar
  58. Willey RL, Maldarelli F, Martin MA, Strebel K (1992a) Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol 66: 7193–7200PubMedGoogle Scholar
  59. Willey RL, Maldarelli F, Martin MA, Strebel K (1992b) Human immunodeficiency virus type 1 vpu protein regulates the formation of intracellular gp160-CD4 complexes. J Virol 66: 226–234PubMedGoogle Scholar
  60. Willey RL, Buckler-White A, Strebel K (1994) Sequences present in the cytoplasmic domain of CD4 are necessary and sufficient to confer sesitivity to the human immunodeficiency virus type 1 Vpu protein. J Virol 68: 1207–1212PubMedGoogle Scholar
  61. Yao X-J, Gottlinger H, Haseltine WA, Cohen EA (1992) Envelope glycoprotein and CD4 independence of vpu-facilitated human immunodeficiency virus type 1 capsid export. J Virol 66: 5119–5126PubMedGoogle Scholar
  62. Yao X-J, Garzon S, Boisvert F, Haseltine WA, Cohen EA (1993) The effect of vpu on HIV-1-induced syncytia formation JAIDS 6: 135–141Google Scholar
  63. Young J, Kane LP, Exley M, Wileman T (1993) Regulation of selective protein degradation in the endoplasmic reticulum by redox potential. J Biol Chem 268: 19810–19818PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • M. Abdul Jabbar
    • 1
  1. 1.Department of Molecular Biology/NC2-133Research Institute, The Cleaveland Clinic FoundationClevelandUSA

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