Skip to main content

Advertisement

SpringerLink
Log in

Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Many proteins and protein regions are disordered in their native, biologically active states. These proteins/regions are abundant in different organisms and carry out important biological functions that complement the functional repertoire of ordered proteins. Viruses, with their highly compact genomes, small proteomes, and high adaptability for fast change in their biological and physical environment utilize many of the advantages of intrinsic disorder. In fact, viral proteins are generally rich in intrinsic disorder, and intrinsically disordered regions are commonly used by viruses to invade the host organisms, to hijack various host systems, and to help viruses in accommodation to their hostile habitats and to manage their economic usage of genetic material. In this review, we focus on the structural peculiarities of HIV-1 proteins, on the abundance of intrinsic disorder in viral proteins, and on the role of intrinsic disorder in their functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19

Similar content being viewed by others

References

  1. Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K, Hart J, Obradovic Z, Kissinger C, Villafranca JE (1998) Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac Symp Biocomput 3:473–484

    Google Scholar 

  2. Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331

    Article  PubMed  CAS  Google Scholar 

  3. Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41(3):415–427

    Article  PubMed  CAS  Google Scholar 

  4. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59

    Article  PubMed  CAS  Google Scholar 

  5. Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27(10):527–533

    Article  PubMed  CAS  Google Scholar 

  6. Daughdrill GW, Pielak GJ, Uversky VN, Cortese MS, Dunker AK (2005) Natively disordered proteins. In: Buchner J, Kiefhaber T (eds) Handbook of protein folding. Wiley-VCH, Verlag GmbH & Co. KGaA, Weinheim, pp 271–353

    Google Scholar 

  7. Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804(6):1231–1264

    PubMed  CAS  Google Scholar 

  8. Dziedzic-Letka A, Rymarczyk G, Kaplon TM, Gorecki A, Szamborska-Gbur A, Wojtas M, Dobryszycki P, Ozyhar A (2011) Intrinsic disorder of Drosophila melanogaster hormone receptor 38 N-terminal domain. Proteins 79(2):376–392

    Article  PubMed  CAS  Google Scholar 

  9. Holt C, Sawyer L (1993) Caseins as rheomorphic proteins: interpretation of primary and secondary structures of the as1-, b-, and k-caseins. J Chem Soc Faraday Trans 89:2683–2692

    Article  CAS  Google Scholar 

  10. Pullen RA, Jenkins JA, Tickle IJ, Wood SP, Blundell TL (1975) The relation of polypeptide hormone structure and flexibility to receptor binding: the relevance of X-ray studies on insulins, glucagon and human placental lactogen. Mol Cell Biochem 8(1):5–20

    Article  PubMed  CAS  Google Scholar 

  11. Cary PD, Moss T, Bradbury EM (1978) High-resolution proton-magnetic-resonance studies of chromatin core particles. Eur J Biochem 89(2):475–482

    Article  PubMed  CAS  Google Scholar 

  12. Linderstrom-Lang K, Schellman JA (1959) Protein structure and enzyme activity. In: Boyer PD, Lardy H, Myrback K (eds) The enzymes, 2nd edn. Academic Press, New York, pp 443–510

    Google Scholar 

  13. Schweers O, Schonbrunn-Hanebeck E, Marx A, Mandelkow E (1994) Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem 269(39):24290–24297

    PubMed  CAS  Google Scholar 

  14. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35(43):13709–13715

    Article  PubMed  CAS  Google Scholar 

  15. Dunker AK, Obradovic Z (2001) The protein trinity–linking function and disorder. Nat Biotechnol 19(9):805–806

    Article  PubMed  CAS  Google Scholar 

  16. Chen J, Liang H, Fernandez A (2008) Protein structure protection commits gene expression patterns. Genome Biol 9(7):R107

    Article  PubMed  CAS  Google Scholar 

  17. Uversky VN (2003) A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders. J Biomol Struct Dyn 21(2):211–234

    PubMed  CAS  Google Scholar 

  18. Uversky VN (2010) Flexible nets of malleable guardians: intrinsically disordered chaperones in neurodegenerative diseases. Chem Rev 111:1134–1166

    Article  PubMed  CAS  Google Scholar 

  19. Toth-Petroczy A, Oldfield CJ, Simon I, Takagi Y, Dunker AK, Uversky VN, Fuxreiter M (2008) Malleable machines in transcription regulation: the mediator complex. PLoS Comput Biol 4(12):e1000243

    Article  PubMed  CAS  Google Scholar 

  20. Fuxreiter M, Tompa P, Simon I, Uversky VN, Hansen JC, Asturias FJ (2008) Malleable machines take shape in eukaryotic transcriptional regulation. Nat Chem Biol 4(12):728–737

    Article  PubMed  CAS  Google Scholar 

  21. Tsvetkov P, Asher G, Paz A, Reuven N, Sussman JL, Silman I, Shaul Y (2008) Operational definition of intrinsically unstructured protein sequences based on susceptibility to the 20S proteasome. Proteins 70(4):1357–1366

    Article  PubMed  CAS  Google Scholar 

  22. Dunker AK, Uversky VN (2010) Drugs for ‘protein clouds’: targeting intrinsically disordered transcription factors. Curr Opin Pharmacol 10(6):782–788

    Article  PubMed  CAS  Google Scholar 

  23. Uversky VN (2010) Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder-based complexes. Chem Soc Rev 40:1623–1635

    Article  PubMed  CAS  Google Scholar 

  24. Livesay DR (2010) Protein dynamics: dancing on an ever-changing free energy stage. Curr Opin Pharmacol 10(6):706–708

    Article  PubMed  CAS  Google Scholar 

  25. Uversky VN (2010) The mysterious unfoldome: structureless, underappreciated, yet vital part of any given proteome. J Biomed Biotechnol 2010:568068

    Article  PubMed  CAS  Google Scholar 

  26. Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11(4):739–756

    Article  PubMed  CAS  Google Scholar 

  27. Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323(3):573–584

    Article  PubMed  CAS  Google Scholar 

  28. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J 272(20):5129–5148

    Article  PubMed  CAS  Google Scholar 

  29. Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18(5):343–384

    Article  PubMed  CAS  Google Scholar 

  30. Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK (2007) Intrinsic disorder and functional proteomics. Biophys J 92(5):1439–1456

    Google Scholar 

  31. Vucetic S, Xie H, Iakoucheva LM, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2007) Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions. J Proteome Res 6(5):1899–1916

    Article  PubMed  CAS  Google Scholar 

  32. Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2007) Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. J Proteome Res 6(5):1917–1932

    Article  PubMed  CAS  Google Scholar 

  33. Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK, Uversky VN, Obradovic Z (2007) Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 6(5):1882–1898

    Article  PubMed  CAS  Google Scholar 

  34. Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246

    Article  PubMed  CAS  Google Scholar 

  35. Lee H, Mok KH, Muhandiram R, Park KH, Suk JE, Kim DH, Chang J, Sung YC, Choi KY, Han KH (2000) Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 275(38):29426–29432

    Article  PubMed  CAS  Google Scholar 

  36. Adkins JN, Lumb KJ (2002) Intrinsic structural disorder and sequence features of the cell cycle inhibitor p57Kip2. Proteins 46(1):1–7

    Article  PubMed  CAS  Google Scholar 

  37. Chang BS, Minn AJ, Muchmore SW, Fesik SW, Thompson CB (1997) Identification of a novel regulatory domain in Bcl-X(L) and Bcl-2. EMBO J 16(5):968–977

    Article  PubMed  CAS  Google Scholar 

  38. Campbell KM, Terrell AR, Laybourn PJ, Lumb KJ (2000) Intrinsic structural disorder of the C-terminal activation domain from the bZIP transcription factor Fos. Biochemistry 39(10):2708–2713

    Article  PubMed  CAS  Google Scholar 

  39. Sunde M, McGrath KC, Young L, Matthews JM, Chua EL, Mackay JP, Death AK (2004) TC-1 is a novel tumorigenic and natively disordered protein associated with thyroid cancer. Cancer Res 64(8):2766–2773

    Article  PubMed  CAS  Google Scholar 

  40. Glenner GG, Wong CW (1984) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135

    Article  PubMed  CAS  Google Scholar 

  41. Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4(11):2757–2763

    PubMed  CAS  Google Scholar 

  42. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251(4994):675–678

    Article  PubMed  CAS  Google Scholar 

  43. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90(23):11282–11286

    Article  PubMed  CAS  Google Scholar 

  44. Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM (1985) Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 35(7):957–961

    PubMed  CAS  Google Scholar 

  45. Dev KK, Hofele K, Barbieri S, Buchman VL, van der Putten H (2003) Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45(1):14–44

    Article  PubMed  CAS  Google Scholar 

  46. Prusiner SB (2001) Shattuck lecture–neurodegenerative diseases and prions. N Engl J Med 344(20):1516–1526

    Article  PubMed  CAS  Google Scholar 

  47. Zoghbi HY, Orr HT (1999) Polyglutamine diseases: protein cleavage and aggregation. Curr Opin Neurobiol 9(5):566–570

    Article  PubMed  CAS  Google Scholar 

  48. Uversky VN, Roman A, Oldfield CJ, Dunker AK (2006) Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. J Proteome Res 5(8):1829–1842

    Article  PubMed  CAS  Google Scholar 

  49. Cheng Y, LeGall T, Oldfield CJ, Dunker AK, Uversky VN (2006) Abundance of intrinsic disorder in protein associated with cardiovascular disease. Biochemistry 45(35):10448–10460

    Article  PubMed  CAS  Google Scholar 

  50. Uversky VN (2008) Amyloidogenesis of natively unfolded proteins. Curr Alzheimer Res 5(3):260–287

    Article  PubMed  CAS  Google Scholar 

  51. Uversky VN (2009) Intrinsic disorder in proteins associated with neurodegenerative diseases. Front Biosci 14:5188–5238

    Article  PubMed  CAS  Google Scholar 

  52. Mohan A, Sullivan WJ Jr, Radivojac P, Dunker AK, Uversky VN (2008) Intrinsic disorder in pathogenic and non-pathogenic microbes: discovering and analyzing the unfoldomes of early branching eukaryotes. Mol Biosyst 4(4):328–340

    Article  PubMed  CAS  Google Scholar 

  53. Midic U, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2008) Protein disorder in the human diseasome: Unfoldomics of human genetic diseases. PLoS Comput Biol (In press)

  54. Uversky VN, Oldfield CJ, Midic U, Xie H, Xue B, Vucetic S, Iakoucheva LM, Obradovic Z, Dunker AK (2009) Unfoldomics of human diseases: linking protein intrinsic disorder with diseases. BMC Genomics 10(Suppl):S7

    Article  PubMed  CAS  Google Scholar 

  55. Koonin EV, Senkevich TG, Dolja VV (2006) The ancient Virus World and evolution of cells. Biol Direct 1:29

    Article  PubMed  CAS  Google Scholar 

  56. Forterre P, Prangishvili D (2009) The origin of viruses. Res Microbiol 160(7):466–472

    Article  PubMed  CAS  Google Scholar 

  57. Prangishvili D, Forterre P, Garrett RA (2006) Viruses of the Archaea: a unifying view. Nat Rev Microbiol 4(11):837–848

    Article  PubMed  CAS  Google Scholar 

  58. Reanney DC (1982) The evolution of RNA viruses. Annu Rev Microbiol 36:47–73

    Article  PubMed  CAS  Google Scholar 

  59. Drake JW, Charlesworth B, Charlesworth D, Crow JF (1998) Rates of spontaneous mutation. Genetics 148(4):1667–1686

    PubMed  CAS  Google Scholar 

  60. Tokuriki N, Oldfield CJ, Uversky VN, Berezovsky IN, Tawfik DS (2009) Do viral proteins possess unique biophysical features? Trends Biochem Sci 34(2):53–59

    Article  PubMed  CAS  Google Scholar 

  61. Vacic V, Uversky VN, Dunker AK, Lonardi S (2007) Composition Profiler: a tool for discovery and visualization of amino acid composition differences. BMC Bioinformatics 8:211

    Article  PubMed  CAS  Google Scholar 

  62. Dunker AK, Obradovic Z, Romero P, Garner EC, Brown CJ (2000) Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 11:161–171

    PubMed  CAS  Google Scholar 

  63. Romero P, Obradovic Z, Kissinger CR, Villafranca JE, Garner E, Guilliot S, Dunker AK (1998) Thousands of proteins likely to have long disordered regions. Pac Symp Biocomput 3:437–448

    Google Scholar 

  64. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337(3):635–645

    Article  PubMed  CAS  Google Scholar 

  65. Oldfield CJ, Cheng Y, Cortese MS, Brown CJ, Uversky VN, Dunker AK (2005) Comparing and combining predictors of mostly disordered proteins. Biochemistry 44(6):1989–2000

    Article  PubMed  CAS  Google Scholar 

  66. Clements JE, Zink MC (1996) Molecular biology and pathogenesis of animal lentivirus infections. Clin Microbiol Rev 9(1):100–117

    PubMed  CAS  Google Scholar 

  67. Goudsmit J (1997) Viral sex: the nature of AIDS. Oxford University Press, New York

    Google Scholar 

  68. Leroux C, Cadore JL, Montelaro RC (2004) Equine infectious anemia virus (EIAV): what has HIV’s country cousin got to tell us? Vet Res 35(4):485–512

    Article  PubMed  CAS  Google Scholar 

  69. Marx PA, Li Y, Lerche NW, Sutjipto S, Gettie A, Yee JA, Brotman BH, Prince AM, Hanson A, Webster RG et al (1991) Isolation of a simian immunodeficiency virus related to human immunodeficiency virus type 2 from a west African pet sooty mangabey. J Virol 65(8):4480–4485

    PubMed  CAS  Google Scholar 

  70. Greene WC (2007) A history of AIDS: looking back to see ahead. Eur J Immunol 37(Suppl 1):S94–S102

    Article  PubMed  CAS  Google Scholar 

  71. Weiss RA (2001) Gulliver’s travels in HIV land. Nature 410(6831):963–967

    Article  PubMed  CAS  Google Scholar 

  72. Coffin JM, Hughes SH, Varmus HE (1997) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  73. Frankel AD, Young JA (1998) HIV-1: fifteen proteins and an RNA. Annu Rev Biochem 67:1–25

    Article  PubMed  CAS  Google Scholar 

  74. Schlessinger A, Punta M, Yachdav G, Kajan L, Rost B (2009) Improved disorder prediction by combination of orthogonal approaches. PLoS One 4(2):e4433

    Article  PubMed  CAS  Google Scholar 

  75. Mizianty MJ, Stach W, Chen K, Kedarisetti KD, Disfani FM, Kurgan L (2010) Improved sequence-based prediction of disordered regions with multilayer fusion of multiple information sources. Bioinformatics 26(18):i489–i496

    Article  PubMed  CAS  Google Scholar 

  76. Mizianty MJ, Zhang T, Xue B, Zhou Y, Dunker AK, Uversky VN, Kurgan L (2011) In-silico prediction of disorder content using hybrid sequence representation. BMC Bioinformatics 12(1):245

  77. Noivirt-Brik O, Prilusky J, Sussman JL (2009) Assessment of disorder predictions in CASP8. Proteins 77(Suppl 9):210–216

    Article  PubMed  CAS  Google Scholar 

  78. Longhi S (2010) Structural disorder in viral proteins. Protein Pept Lett 17(8):930–931

    Article  PubMed  CAS  Google Scholar 

  79. Uversky VN, Longhi S (eds) (2012) Flexible viruses structural disorder in viral proteins. The Wiley Protein and Peptide Science Series John Wiley and Sons, Hoboken, New Jersey

    Google Scholar 

  80. Xue B, Oldfield CJ, Dunker AK, Uversky VN (2009) CDF it all: consensus prediction of intrinsically disordered proteins based on various cumulative distribution functions. FEBS Lett 583(9):1469–1474

    Article  PubMed  CAS  Google Scholar 

  81. Bienkiewicz EA, Adkins JN, Lumb KJ (2002) Functional consequences of preorganized helical structure in the intrinsically disordered cell-cycle inhibitor p27(Kip1). Biochemistry 41(3):752–759

    Article  PubMed  CAS  Google Scholar 

  82. Chi SW, Kim DH, Lee SH, Chang I, Han KH (2007) Pre-structured motifs in the natively unstructured preS1 surface antigen of hepatitis B virus. Protein Sci 16(10):2108–2117

    Article  PubMed  CAS  Google Scholar 

  83. Ramelot TA, Gentile LN, Nicholson LK (2000) Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors. Biochemistry 39(10):2714–2725

    Article  PubMed  CAS  Google Scholar 

  84. Sayers EW, Gerstner RB, Draper DE, Torchia DA (2000) Structural preordering in the N-terminal region of ribosomal protein S4 revealed by heteronuclear NMR spectroscopy. Biochemistry 39(44):13602–13613

    Article  PubMed  CAS  Google Scholar 

  85. Zitzewitz JA, Ibarra-Molero B, Fishel DR, Terry KL, Matthews CR (2000) Preformed secondary structure drives the association reaction of GCN4–p1, a model coiled-coil system. J Mol Biol 296(4):1105–1116

    Article  PubMed  CAS  Google Scholar 

  86. Jensen MR, Blackledge M (2008) On the origin of NMR dipolar waves in transient helical elements of partially folded proteins. J Am Chem Soc 130(34):11266–11267

    Article  PubMed  CAS  Google Scholar 

  87. Jensen MR, Houben K, Lescop E, Blanchard L, Ruigrok RW, Blackledge M (2008) Quantitative conformational analysis of partially folded proteins from residual dipolar couplings: application to the molecular recognition element of Sendai virus nucleoprotein. J Am Chem Soc 130(25):8055–8061

    Article  PubMed  CAS  Google Scholar 

  88. Jensen MR, Communie G, Ribeiro EA Jr, Martinez N, Desfosses A, Salmon L, Mollica L, Gabel F, Jamin M, Longhi S, Ruigrok RW, Blackledge M (2011) Intrinsic disorder in measles virus nucleocapsids. Proc Natl Acad Sci USA 108(24):9839–9844

    Article  PubMed  CAS  Google Scholar 

  89. Garner E, Romero P, Dunker AK, Brown C, Obradovic Z (1999) Predicting binding regions within disordered proteins. Genome Inform Ser Workshop Genome Inform 10:41–50

    PubMed  CAS  Google Scholar 

  90. Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44(37):12454–12470

    Article  PubMed  CAS  Google Scholar 

  91. Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK (2007) Mining alpha-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46(47):13468–13477

    Article  PubMed  CAS  Google Scholar 

  92. Zhu P, Liu J, Bess J Jr, Chertova E, Lifson JD, Grise H, Ofek GA, Taylor KA, Roux KH (2006) Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441(7095):847–852

    Article  PubMed  CAS  Google Scholar 

  93. Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89(2):263–273

    Article  PubMed  CAS  Google Scholar 

  94. Liu J, Bartesaghi A, Borgnia MJ, Sapiro G, Subramaniam S (2008) Molecular architecture of native HIV-1 gp120 trimers. Nature 455(7209):109–113

    Article  PubMed  CAS  Google Scholar 

  95. Freed EO, Martin MA (1995) The role of human immunodeficiency virus type 1 envelope glycoproteins in virus infection. J Biol Chem 270(41):23883–23886

    Article  PubMed  CAS  Google Scholar 

  96. Freed EO, Myers DJ, Risser R (1989) Mutational analysis of the cleavage sequence of the human immunodeficiency virus type 1 envelope glycoprotein precursor gp160. J Virol 63(11):4670–4675

    PubMed  CAS  Google Scholar 

  97. McCune JM, Rabin LB, Feinberg MB, Lieberman M, Kosek JC, Reyes GR, Weissman IL (1988) Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. Cell 53(1):55–67

    Article  PubMed  CAS  Google Scholar 

  98. Colman PM, Lawrence MC (2003) The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 4(4):309–319

    Article  PubMed  CAS  Google Scholar 

  99. Dalgleish AG, Beverley PC, 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(5996):763–767

    Article  PubMed  CAS  Google Scholar 

  100. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85(7):1135–1148

    Article  PubMed  CAS  Google Scholar 

  101. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381(6584):661–666

    Article  PubMed  CAS  Google Scholar 

  102. Chan DC, Kim PS (1998) HIV entry and its inhibition. Cell 93(5):681–684

    Article  PubMed  CAS  Google Scholar 

  103. Gallo SA, Finnegan CM, Viard M, Raviv Y, Dimitrov A, Rawat SS, Puri A, Durell S, Blumenthal R (2003) The HIV Env-mediated fusion reaction. Biochim Biophys Acta 1614(1):36–50

    Article  PubMed  CAS  Google Scholar 

  104. Ugolini S, Mondor I, Sattentau QJ (1999) HIV-1 attachment: another look. Trends Microbiol 7(4):144–149

    Article  PubMed  CAS  Google Scholar 

  105. Karlsson Hedestam GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT (2008) The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol 6(2):143–155

    Article  PubMed  CAS  Google Scholar 

  106. Allan JS, Coligan JE, Barin F, McLane MF, Sodroski JG, Rosen CA, Haseltine WA, Lee TH, Essex M (1985) Major glycoprotein antigens that induce antibodies in AIDS patients are encoded by HTLV-III. Science 228(4703):1091–1094

    Article  PubMed  CAS  Google Scholar 

  107. Kowalski M, Potz J, Basiripour L, Dorfman T, Goh WC, Terwilliger E, Dayton A, Rosen C, Haseltine W, Sodroski J (1987) Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 237(4820):1351–1355

    Article  PubMed  CAS  Google Scholar 

  108. Lasky LA, Nakamura G, Smith DH, Fennie C, Shimasaki C, Patzer E, Berman P, Gregory T, Capon DJ (1987) Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell 50(6):975–985

    Article  PubMed  CAS  Google Scholar 

  109. Olshevsky U, Helseth E, Furman C, Li J, Haseltine W, Sodroski J (1990) Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. J Virol 64(12):5701–5707

    PubMed  CAS  Google Scholar 

  110. Trkola A, Dragic T, Arthos J, Binley JM, Olson WC, Allaway GP, Cheng-Mayer C, Robinson J, Maddon PJ, Moore JP (1996) CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384(6605):184–187

    Article  PubMed  CAS  Google Scholar 

  111. Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384(6605):179–183

    Article  PubMed  CAS  Google Scholar 

  112. Freed EO, Myers DJ, Risser R (1991) Identification of the principal neutralizing determinant of human immunodeficiency virus type 1 as a fusion domain. J Virol 65(1):190–194

    PubMed  CAS  Google Scholar 

  113. Groenink M, Fouchier RA, Broersen S, Baker CH, Koot M, van’t Wout AB, Huisman HG, Miedema F, Tersmette M, Schuitemaker H (1993) Relation of phenotype evolution of HIV-1 to envelope V2 configuration. Science 260(5113):1513–1516

    Article  PubMed  CAS  Google Scholar 

  114. Gu R, Westervelt P, Ratner L (1993) Role of HIV-1 envelope V3 loop cleavage in cell tropism. AIDS Res Hum Retroviruses 9(10):1007–1015

    Article  PubMed  CAS  Google Scholar 

  115. Ebenbichler C, Westervelt P, Carrillo A, Henkel T, Johnson D, Ratner L (1993) Structure-function relationships of the HIV-1 envelope V3 loop tropism determinant: evidence for two distinct conformations. Aids 7(5):639–646

    Article  PubMed  CAS  Google Scholar 

  116. Koito A, Harrowe G, Levy JA, Cheng-Mayer C (1994) Functional role of the V1/V2 region of human immunodeficiency virus type 1 envelope glycoprotein gp120 in infection of primary macrophages and soluble CD4 neutralization. J Virol 68(4):2253–2259

    PubMed  CAS  Google Scholar 

  117. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393(6686):648–659

    Article  PubMed  CAS  Google Scholar 

  118. Kwong PD, Wyatt R, Majeed S, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (2000) Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates. Structure 8(12):1329–1339

    Article  PubMed  CAS  Google Scholar 

  119. Liu SQ, Liu SX, Fu YX (2008) Molecular motions of human HIV-1 gp120 envelope glycoproteins. J Mol Model 14(9):857–870

    Article  PubMed  CAS  Google Scholar 

  120. Kong L, Huang CC, Coales SJ, Molnar KS, Skinner J, Hamuro Y, Kwong PD (2010) Local conformational stability of HIV-1 gp120 in unliganded and CD4-bound states as defined by amide hydrogen/deuterium exchange. J Virol 84(19):10311–10321

    Article  PubMed  CAS  Google Scholar 

  121. Pancera M, Majeed S, Ban YE, Chen L, Huang CC, Kong L, Kwon YD, Stuckey J, Zhou T, Robinson JE, Schief WR, Sodroski J, Wyatt R, Kwong PD (2010) Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc Natl Acad Sci USA 107(3):1166–1171

    Article  PubMed  CAS  Google Scholar 

  122. Gallaher WR, Ball JM, Garry RF, Griffin MC, Montelaro RC (1989) A general model for the transmembrane proteins of HIV and other retroviruses. AIDS Res Hum Retroviruses 5(4):431–440

    Article  PubMed  CAS  Google Scholar 

  123. Cleveland SM, McLain L, Cheung L, Jones TD, Hollier M, Dimmock NJ (2003) A region of the C-terminal tail of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 contains a neutralizing epitope: evidence for its exposure on the surface of the virion. J Gen Virol 84(Pt 3):591–602

    Article  PubMed  CAS  Google Scholar 

  124. Cheung L, McLain L, Hollier MJ, Reading SA, Dimmock NJ (2005) Part of the C-terminal tail of the envelope gp41 transmembrane glycoprotein of human immunodeficiency virus type 1 is exposed on the surface of infected cells and is involved in virus-mediated cell fusion. J Gen Virol 86(Pt 1):131–138

    Article  PubMed  CAS  Google Scholar 

  125. Sattentau QJ, Moore JP (1991) Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J Exp Med 174(2):407–415

    Article  PubMed  CAS  Google Scholar 

  126. Sattentau QJ, Moore JP (1993) The role of CD4 in HIV binding and entry. Philos Trans R Soc Lond B Biol Sci 342(1299):59–66

    Article  PubMed  CAS  Google Scholar 

  127. Sattentau QJ, Moore JP, Vignaux F, Traincard F, Poignard P (1993) Conformational changes induced in the envelope glycoproteins of the human and simian immunodeficiency viruses by soluble receptor binding. J Virol 67(12):7383–7393

    PubMed  CAS  Google Scholar 

  128. Sullivan N, Sun Y, Li J, Hofmann W, Sodroski J (1995) Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T cell line-passaged human immunodeficiency virus type 1 isolates. J Virol 69(7):4413–4422

    PubMed  CAS  Google Scholar 

  129. Allan JS, Strauss J, Buck DW (1990) Enhancement of SIV infection with soluble receptor molecules. Science 247(4946):1084–1088

    Article  PubMed  CAS  Google Scholar 

  130. Weissenhorn W, Calder LJ, Dessen A, Laue T, Skehel JJ, Wiley DC (1997) Assembly of a rod-shaped chimera of a trimeric GCN4 zipper and the HIV-1 gp41 ectodomain expressed in Escherichia coli. Proc Natl Acad Sci USA 94(12):6065–6069

    Article  PubMed  CAS  Google Scholar 

  131. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC (1997) Atomic structure of the ectodomain from HIV-1 gp41. Nature 387(6631):426–430

    Article  PubMed  CAS  Google Scholar 

  132. Caffrey M, Cai M, Kaufman J, Stahl SJ, Wingfield PT, Covell DG, Gronenborn AM, Clore GM (1998) Three-dimensional solution structure of the 44 kDa ectodomain of SIV gp41. EMBO J 17(16):4572–4584

    Article  PubMed  CAS  Google Scholar 

  133. Tan K, Liu J, Wang J, Shen S, Lu M (1997) Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc Natl Acad Sci USA 94(23):12303–12308

    Article  PubMed  CAS  Google Scholar 

  134. Skehel JJ, Wiley DC (1998) Coiled coils in both intracellular vesicle and viral membrane fusion. Cell 95(7):871–874

    Article  PubMed  CAS  Google Scholar 

  135. Li X, Romero P, Rani M, Dunker AK, Obradovic Z (1999) Predicting protein disorder for N-, C-, and internal regions. Genome Inform Ser Workshop Genome Inform 10:30–40

    PubMed  CAS  Google Scholar 

  136. Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42(1):38–48

    Article  PubMed  CAS  Google Scholar 

  137. Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics 7:208

    Article  PubMed  CAS  Google Scholar 

  138. Kwong PD, Wyatt R, Sattentau QJ, Sodroski J, Hendrickson WA (2000) Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus. J Virol 74(4):1961–1972

    Article  PubMed  CAS  Google Scholar 

  139. Carr CM, Kim PS (1993) A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 73(4):823–832

    Article  PubMed  CAS  Google Scholar 

  140. Gheysen D, Jacobs E, de Foresta F, Thiriart C, Francotte M, Thines D, De Wilde M (1989) Assembly and release of HIV-1 precursor Pr55gag virus-like particles from recombinant baculovirus-infected insect cells. Cell 59(1):103–112

    Article  PubMed  CAS  Google Scholar 

  141. Wills JW, Craven RC (1991) Form, function, and use of retroviral gag proteins. Aids 5(6):639–654

    Article  PubMed  CAS  Google Scholar 

  142. Campbell S, Rein A (1999) In vitro assembly properties of human immunodeficiency virus type 1 Gag protein lacking the p6 domain. J Virol 73(3):2270–2279

    PubMed  CAS  Google Scholar 

  143. Gross I, Hohenberg H, Wilk T, Wiegers K, Grattinger M, Muller B, Fuller S, Krausslich HG (2000) A conformational switch controlling HIV-1 morphogenesis. EMBO J 19(1):103–113

    Article  PubMed  CAS  Google Scholar 

  144. Campbell S, Fisher RJ, Towler EM, Fox S, Issaq HJ, Wolfe T, Phillips LR, Rein A (2001) Modulation of HIV-like particle assembly in vitro by inositol phosphates. Proc Natl Acad Sci USA 98(19):10875–10879

    Article  PubMed  CAS  Google Scholar 

  145. Resh MD (2005) Intracellular trafficking of HIV-1 Gag: how Gag interacts with cell membranes and makes viral particles. AIDS Rev 7(2):84–91

    PubMed  Google Scholar 

  146. Bieniasz PD (2006) Late budding domains and host proteins in enveloped virus release. Virology 344(1):55–63

    Article  PubMed  CAS  Google Scholar 

  147. Klein KC, Reed JC, Lingappa JR (2007) Intracellular destinies: degradation, targeting, assembly, and endocytosis of HIV Gag. AIDS Rev 9(3):150–161

    PubMed  Google Scholar 

  148. Williams RL, Urbe S (2007) The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol 8(5):355–368

    Article  PubMed  CAS  Google Scholar 

  149. Ganser-Pornillos BK, Yeager M, Sundquist WI (2008) The structural biology of HIV assembly. Curr Opin Struct Biol 18(2):203–217

    Article  PubMed  CAS  Google Scholar 

  150. Gelderblom HR (1991) Assembly and morphology of HIV: potential effect of structure on viral function. Aids 5(6):617–637

    Article  PubMed  CAS  Google Scholar 

  151. Freed EO (1998) HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 251(1):1–15

    Article  PubMed  CAS  Google Scholar 

  152. Gottlinger HG, Sodroski JG, Haseltine WA (1989) Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 86(15):5781–5785

    Article  PubMed  CAS  Google Scholar 

  153. Bryant M, Ratner L (1990) Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc Natl Acad Sci USA 87(2):523–527

    Article  PubMed  CAS  Google Scholar 

  154. Morikawa Y, Zhang WH, Hockley DJ, Nermut MV, Jones IM (1998) Detection of a trimeric human immunodeficiency virus type 1 Gag intermediate is dependent on sequences in the matrix protein, p17. J Virol 72(9):7659–7663

    PubMed  CAS  Google Scholar 

  155. Tang C, Loeliger E, Luncsford P, Kinde I, Beckett D, Summers MF (2004) Entropic switch regulates myristate exposure in the HIV-1 matrix protein. Proc Natl Acad Sci USA 101(2):517–522

    Article  PubMed  CAS  Google Scholar 

  156. Hill CP, Worthylake D, Bancroft DP, Christensen AM, Sundquist WI (1996) Crystal structures of the trimeric human immunodeficiency virus type 1 matrix protein: implications for membrane association and assembly. Proc Natl Acad Sci USA 93(7):3099–3104

    Article  PubMed  CAS  Google Scholar 

  157. Alfadhli A, Barklis RL, Barklis E (2009) HIV-1 matrix organizes as a hexamer of trimers on membranes containing phosphatidylinositol-(4, 5)-bisphosphate. Virology 387(2):466–472

    Article  PubMed  CAS  Google Scholar 

  158. Massiah MA, Starich MR, Paschall C, Summers MF, Christensen AM, Sundquist WI (1994) Three-dimensional structure of the human immunodeficiency virus type 1 matrix protein. J Mol Biol 244(2):198–223

    Article  PubMed  CAS  Google Scholar 

  159. Matthews S, Barlow P, Boyd J, Barton G, Russell R, Mills H, Cunningham M, Meyers N, Burns N, Clark N et al (1994) Structural similarity between the p17 matrix protein of HIV-1 and interferon-gamma. Nature 370(6491):666–668

    Article  PubMed  CAS  Google Scholar 

  160. Dingwall C, Laskey RA (1991) Nuclear targeting sequences–a consensus? Trends Biochem Sci 16(12):478–481

    Article  PubMed  CAS  Google Scholar 

  161. Riviere L, Darlix JL, Cimarelli A (2010) Analysis of the viral elements required in the nuclear import of HIV-1 DNA. J Virol 84(2):729–739

    Article  PubMed  CAS  Google Scholar 

  162. Spearman P, Horton R, Ratner L, Kuli-Zade I (1997) Membrane binding of human immunodeficiency virus type 1 matrix protein in vivo supports a conformational myristyl switch mechanism. J Virol 71(9):6582–6592

    PubMed  CAS  Google Scholar 

  163. Saad JS, Miller J, Tai J, Kim A, Ghanam RH, Summers MF (2006) Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc Natl Acad Sci USA 103(30):11364–11369

    Article  PubMed  CAS  Google Scholar 

  164. Hearps AC, Wagstaff KM, Piller SC, Jans DA (2008) The N-terminal basic domain of the HIV-1 matrix protein does not contain a conventional nuclear localization sequence but is required for DNA binding and protein self-association. Biochemistry 47(7):2199–2210

    Article  PubMed  CAS  Google Scholar 

  165. Cai M, Huang Y, Craigie R, Clore GM (2010) Structural basis of the association of HIV-1 matrix protein with DNA. PLoS One 5(12):e15675

    Article  PubMed  CAS  Google Scholar 

  166. Pornillos O, Ganser-Pornillos BK, Kelly BN, Hua Y, Whitby FG, Stout CD, Sundquist WI, Hill CP, Yeager M (2009) X-ray structures of the hexameric building block of the HIV capsid. Cell 137(7):1282–1292

    Article  PubMed  Google Scholar 

  167. Mateu MG (2009) The capsid protein of human immunodeficiency virus: intersubunit interactions during virus assembly. FEBS J 276(21):6098–6109

    Article  PubMed  CAS  Google Scholar 

  168. Gamble TR, Yoo S, Vajdos FF, von Schwedler UK, Worthylake DK, Wang H, McCutcheon JP, Sundquist WI, Hill CP (1997) Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein. Science 278(5339):849–853

    Article  PubMed  CAS  Google Scholar 

  169. Worthylake DK, Wang H, Yoo S, Sundquist WI, Hill CP (1999) Structures of the HIV-1 capsid protein dimerization domain at 2.6 A resolution. Acta Crystallogr D Biol Crystallogr 55(Pt 1):85–92

    Article  PubMed  CAS  Google Scholar 

  170. Momany C, Kovari LC, Prongay AJ, Keller W, Gitti RK, Lee BM, Gorbalenya AE, Tong L, McClure J, Ehrlich LS, Summers MF, Carter C, Rossmann MG (1996) Crystal structure of dimeric HIV-1 capsid protein. Nat Struct Biol 3(9):763–770

    Article  PubMed  CAS  Google Scholar 

  171. Gitti RK, Lee BM, Walker J, Summers MF, Yoo S, Sundquist WI (1996) Structure of the amino-terminal core domain of the HIV-1 capsid protein. Science 273(5272):231–235

    Article  PubMed  CAS  Google Scholar 

  172. Berthet-Colominas C, Monaco S, Novelli A, Sibai G, Mallet F, Cusack S (1999) Head-to-tail dimers and interdomain flexibility revealed by the crystal structure of HIV-1 capsid protein (p24) complexed with a monoclonal antibody Fab. EMBO J 18(5):1124–1136

    Article  PubMed  CAS  Google Scholar 

  173. Ganser-Pornillos BK, Cheng A, Yeager M (2007) Structure of full-length HIV-1 CA: a model for the mature capsid lattice. Cell 131(1):70–79

    Article  PubMed  CAS  Google Scholar 

  174. Srinivasakumar N, Hammarskjold ML, Rekosh D (1995) Characterization of deletion mutations in the capsid region of human immunodeficiency virus type 1 that affect particle formation and Gag-Pol precursor incorporation. J Virol 69(10):6106–6114

    PubMed  CAS  Google Scholar 

  175. Ebbets-Reed D, Scarlata S, Carter CA (1996) The major homology region of the HIV-1 gag precursor influences membrane affinity. Biochemistry 35(45):14268–14275

    Article  PubMed  CAS  Google Scholar 

  176. Gamble TR, Vajdos FF, Yoo S, Worthylake DK, Houseweart M, Sundquist WI, Hill CP (1996) Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87(7):1285–1294

    Article  PubMed  CAS  Google Scholar 

  177. Sokolskaja E, Sayah DM, Luban J (2004) Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J Virol 78(23):12800–12808

    Article  PubMed  CAS  Google Scholar 

  178. Towers GJ, Hatziioannou T, Cowan S, Goff SP, Luban J, Bieniasz PD (2003) Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat Med 9(9):1138–1143

    Article  PubMed  CAS  Google Scholar 

  179. Owens CM, Song B, Perron MJ, Yang PC, Stremlau M, Sodroski J (2004) Binding and susceptibility to postentry restriction factors in monkey cells are specified by distinct regions of the human immunodeficiency virus type 1 capsid. J Virol 78(10):5423–5437

    Article  PubMed  CAS  Google Scholar 

  180. Hatziioannou T, Perez-Caballero D, Cowan S, Bieniasz PD (2005) Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells. J Virol 79(1):176–183

    Article  PubMed  CAS  Google Scholar 

  181. Berthoux L, Sebastian S, Sokolskaja E, Luban J (2005) Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells. Proc Natl Acad Sci USA 102(41):14849–14853

    Article  PubMed  CAS  Google Scholar 

  182. Kelly BN, Howard BR, Wang H, Robinson H, Sundquist WI, Hill CP (2006) Implications for viral capsid assembly from crystal structures of HIV-1 Gag(1–278) and CA(N)(133–278). Biochemistry 45(38):11257–11266

    Article  PubMed  CAS  Google Scholar 

  183. Schmalzbauer E, Strack B, Dannull J, Guehmann S, Moelling K (1996) Mutations of basic amino acids of NCp7 of human immunodeficiency virus type 1 affect RNA binding in vitro. J Virol 70(2):771–777

    PubMed  CAS  Google Scholar 

  184. Poon DT, Wu J, Aldovini A (1996) Charged amino acid residues of human immunodeficiency virus type 1 nucleocapsid p7 protein involved in RNA packaging and infectivity. J Virol 70(10):6607–6616

    PubMed  CAS  Google Scholar 

  185. Summers MF, Henderson LE, Chance MR, Bess JW Jr, South TL, Blake PR, Sagi I, Perez-Alvarado G, Sowder RC 3rd, Hare DR et al (1992) Nucleocapsid zinc fingers detected in retroviruses: EXAFS studies of intact viruses and the solution-state structure of the nucleocapsid protein from HIV-1. Protein Sci 1(5):563–574

    Article  PubMed  CAS  Google Scholar 

  186. Morellet N, Jullian N, De Rocquigny H, Maigret B, Darlix JL, Roques BP (1992) Determination of the structure of the nucleocapsid protein NCp7 from the human immunodeficiency virus type 1 by 1H NMR. EMBO J 11(8):3059–3065

    PubMed  CAS  Google Scholar 

  187. Huang Y, Khorchid A, Wang J, Parniak MA, Darlix JL, Wainberg MA, Kleiman L (1997) Effect of mutations in the nucleocapsid protein (NCp7) upon Pr160(gag-pol) and tRNA(Lys) incorporation into human immunodeficiency virus type 1. J Virol 71(6):4378–4384

    PubMed  CAS  Google Scholar 

  188. Guo J, Henderson LE, Bess J, Kane B, Levin JG (1997) Human immunodeficiency virus type 1 nucleocapsid protein promotes efficient strand transfer and specific viral DNA synthesis by inhibiting TAR-dependent self-priming from minus-strand strong-stop DNA. J Virol 71(7):5178–5188

    PubMed  CAS  Google Scholar 

  189. Cameron CE, Ghosh M, Le Grice SF, Benkovic SJ (1997) Mutations in HIV reverse transcriptase which alter RNase H activity and decrease strand transfer efficiency are suppressed by HIV nucleocapsid protein. Proc Natl Acad Sci USA 94(13):6700–6705

    Article  PubMed  CAS  Google Scholar 

  190. Carteau S, Batson SC, Poljak L, Mouscadet JF, de Rocquigny H, Darlix JL, Roques BP, Kas E, Auclair C (1997) Human immunodeficiency virus type 1 nucleocapsid protein specifically stimulates Mg2+-dependent DNA integration in vitro. J Virol 71(8):6225–6229

    PubMed  CAS  Google Scholar 

  191. Fossen T, Wray V, Bruns K, Rachmat J, Henklein P, Tessmer U, Maczurek A, Klinger P, Schubert U (2005) Solution structure of the human immunodeficiency virus type 1 p6 protein. J Biol Chem 280(52):42515–42527

    Article  PubMed  CAS  Google Scholar 

  192. Accola MA, Ohagen A, Gottlinger HG (2000) Isolation of human immunodeficiency virus type 1 cores: retention of Vpr in the absence of p6(gag). J Virol 74(13):6198–6202

    Article  PubMed  CAS  Google Scholar 

  193. Welker R, Hohenberg H, Tessmer U, Huckhagel C, Krausslich HG (2000) Biochemical and structural analysis of isolated mature cores of human immunodeficiency virus type 1. J Virol 74(3):1168–1177

    Article  PubMed  CAS  Google Scholar 

  194. Yu XF, Matsuda Z, Yu QC, Lee TH, Essex M (1995) Role of the C terminus Gag protein in human immunodeficiency virus type 1 virion assembly and maturation. J Gen Virol 76(Pt 12):3171–3179

    Article  PubMed  CAS  Google Scholar 

  195. Gottlinger HG, Dorfman T, Sodroski JG, Haseltine WA (1991) Effect of mutations affecting the p6 gag protein on human immunodeficiency virus particle release. Proc Natl Acad Sci USA 88(8):3195–3199

    Article  PubMed  CAS  Google Scholar 

  196. Huang M, Orenstein JM, Martin MA, Freed EO (1995) p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J Virol 69(11):6810–6818

    PubMed  CAS  Google Scholar 

  197. Kondo E, Mammano F, Cohen EA, Gottlinger HG (1995) The p6gag domain of human immunodeficiency virus type 1 is sufficient for the incorporation of Vpr into heterologous viral particles. J Virol 69(5):2759–2764

    PubMed  CAS  Google Scholar 

  198. Yu XF, Dawson L, Tian CJ, Flexner C, Dettenhofer M (1998) Mutations of the human immunodeficiency virus type 1 p6Gag domain result in reduced retention of Pol proteins during virus assembly. J Virol 72(4):3412–3417

    PubMed  CAS  Google Scholar 

  199. Garnier L, Ratner L, Rovinski B, Cao SX, Wills JW (1998) Particle size determinants in the human immunodeficiency virus type 1 Gag protein. J Virol 72(6):4667–4677

    PubMed  CAS  Google Scholar 

  200. Muller B, Patschinsky T, Krausslich HG (2002) The late-domain-containing protein p6 is the predominant phosphoprotein of human immunodeficiency virus type 1 particles. J Virol 76(3):1015–1024

    Article  PubMed  CAS  Google Scholar 

  201. Hemonnot B, Cartier C, Gay B, Rebuffat S, Bardy M, Devaux C, Boyer V, Briant L (2004) The host cell MAP kinase ERK-2 regulates viral assembly and release by phosphorylating the p6gag protein of HIV-1. J Biol Chem 279(31):32426–32434

    Article  PubMed  CAS  Google Scholar 

  202. Stys D, Blaha I, Strop P (1993) Structural and functional studies in vitro on the p6 protein from the HIV-1 gag open reading frame. Biochim Biophys Acta 1182(2):157–161

    PubMed  CAS  Google Scholar 

  203. Strack B, Calistri A, Craig S, Popova E, Gottlinger HG (2003) AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 114(6):689–699

    Article  PubMed  CAS  Google Scholar 

  204. Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK (2004) The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 32(3):1037–1049

    Article  PubMed  CAS  Google Scholar 

  205. Leiherer A, Ludwig C, Wagner R (2009) Uncoupling human immunodeficiency virus type 1 Gag and Pol reading frames: role of the transframe protein p6* in viral replication. J Virol 83(14):7210–7220

    Article  PubMed  CAS  Google Scholar 

  206. Chatterjee A, Mridula P, Mishra RK, Mittal R, Hosur RV (2005) Folding regulates autoprocessing of HIV-1 protease precursor. J Biol Chem 280(12):11369–11378

    Article  PubMed  CAS  Google Scholar 

  207. Dautin N, Karimova G, Ladant D (2003) Human immunodeficiency virus (HIV) type 1 transframe protein can restore activity to a dimerization-deficient HIV protease variant. J Virol 77(15):8216–8226

    Article  PubMed  CAS  Google Scholar 

  208. Louis JM, Dyda F, Nashed NT, Kimmel AR, Davies DR (1998) Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease. Biochemistry 37(8):2105–2110

    Article  PubMed  CAS  Google Scholar 

  209. Candotti D, Chappey C, Rosenheim M, M’Pele P, Huraux JM, Agut H (1994) High variability of the gag/pol transframe region among HIV-1 isolates. C R Acad Sci III 317(2):183–189

    PubMed  CAS  Google Scholar 

  210. Leiherer A, Ludwig C, Wagner R (2009) Influence of extended mutations of the HIV-1 transframe protein p6 on Nef-dependent viral replication and infectivity in vitro. Virology 387(1):200–210

    Article  PubMed  CAS  Google Scholar 

  211. Paulus C, Ludwig C, Wagner R (2004) Contribution of the Gag-Pol transframe domain p6* and its coding sequence to morphogenesis and replication of human immunodeficiency virus type 1. Virology 330(1):271–283

    Article  PubMed  CAS  Google Scholar 

  212. Beissinger M, Paulus C, Bayer P, Wolf H, Rosch P, Wagner R (1996) Sequence-specific resonance assignments of the 1H-NMR spectra and structural characterization in solution of the HIV-1 transframe protein p6. Eur J Biochem 237(2):383–392

    Article  PubMed  CAS  Google Scholar 

  213. Swanstrom R, Wills JW (1997) Synthesis, assembly, and processing of viral proteins. In: Coffin H, Varmus HE (eds) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 263–334

    Google Scholar 

  214. Zybarth G, Carter C (1995) Domains upstream of the protease (PR) in human immunodeficiency virus type 1 Gag-Pol influence PR autoprocessing. J Virol 69(6):3878–3884

    PubMed  CAS  Google Scholar 

  215. Wlodawer A, Erickson JW (1993) Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem 62:543–585

    Article  PubMed  CAS  Google Scholar 

  216. Xie D, Gulnik S, Gustchina E, Yu B, Shao W, Qoronfleh W, Nathan A, Erickson JW (1999) Drug resistance mutations can effect dimer stability of HIV-1 protease at neutral pH. Protein Sci 8(8):1702–1707

    Article  PubMed  CAS  Google Scholar 

  217. Ishima R, Ghirlando R, Tozser J, Gronenborn AM, Torchia DA, Louis JM (2001) Folded monomer of HIV-1 protease. J Biol Chem 276(52):49110–49116

    Article  PubMed  CAS  Google Scholar 

  218. Noel AF, Bilsel O, Kundu A, Wu Y, Zitzewitz JA, Matthews CR (2009) The folding free-energy surface of HIV-1 protease: insights into the thermodynamic basis for resistance to inhibitors. J Mol Biol 387(4):1002–1016

    Article  PubMed  CAS  Google Scholar 

  219. Ishima R, Torchia DA, Lynch SM, Gronenborn AM, Louis JM (2003) Solution structure of the mature HIV-1 protease monomer: insight into the tertiary fold and stability of a precursor. J Biol Chem 278(44):43311–43319

    Article  PubMed  CAS  Google Scholar 

  220. Temin HM (1993) Retrovirus variation and reverse transcription: abnormal strand transfers result in retrovirus genetic variation. Proc Natl Acad Sci USA 90(15):6900–6903

    Article  PubMed  CAS  Google Scholar 

  221. Pathak VK, Hu W-S (1997) “Might as well jump!” Template switching by retroviral reverse transcriptase, defective genome formation, and recombination. Semin Virol 8:141–150

    Article  CAS  Google Scholar 

  222. Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69(8):5087–5094

    PubMed  CAS  Google Scholar 

  223. Freed EO (2001) HIV-1 replication. Somat Cell Mol Genet 26(1–6):13–33

    Article  PubMed  CAS  Google Scholar 

  224. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256(5065):1783–1790

    Article  PubMed  CAS  Google Scholar 

  225. Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P et al (1993) Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci USA 90(13):6320–6324

    Article  PubMed  CAS  Google Scholar 

  226. Bahar I, Erman B, Jernigan RL, Atilgan AR, Covell DG (1999) Collective motions in HIV-1 reverse transcriptase: examination of flexibility and enzyme function. J Mol Biol 285(3):1023–1037

    Article  PubMed  CAS  Google Scholar 

  227. Seckler JM, Howard KJ, Barkley MD, Wintrode PL (2009) Solution structural dynamics of HIV-1 reverse transcriptase heterodimer. Biochemistry 48(32):7646–7655

    Article  PubMed  CAS  Google Scholar 

  228. Liu S, Abbondanzieri EA, Rausch JW, Le Grice SF, Zhuang X (2008) Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates. Science 322(5904):1092–1097

    Article  PubMed  CAS  Google Scholar 

  229. Abbondanzieri EA, Bokinsky G, Rausch JW, Zhang JX, Le Grice SF, Zhuang X (2008) Dynamic binding orientations direct activity of HIV reverse transcriptase. Nature 453(7192):184–189

    Article  PubMed  CAS  Google Scholar 

  230. Pari K, Mueller GA, DeRose EF, Kirby TW, London RE (2003) Solution structure of the RNase H domain of the HIV-1 reverse transcriptase in the presence of magnesium. Biochemistry 42(3):639–650

    Article  PubMed  CAS  Google Scholar 

  231. Chen H, Wei SQ, Engelman A (1999) Multiple integrase functions are required to form the native structure of the human immunodeficiency virus type I intasome. J Biol Chem 274(24):17358–17364

    Article  PubMed  CAS  Google Scholar 

  232. Wei SQ, Mizuuchi K, Craigie R (1997) A large nucleoprotein assembly at the ends of the viral DNA mediates retroviral DNA integration. EMBO J 16(24):7511–7520

    Article  PubMed  CAS  Google Scholar 

  233. Katz RA, Skalka AM (1994) The retroviral enzymes. Annu Rev Biochem 63:133–173

    Article  PubMed  CAS  Google Scholar 

  234. Lataillade M, Kozal MJ (2006) The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 20(7):489–501

    Article  PubMed  Google Scholar 

  235. Pommier Y, Johnson AA, Marchand C (2005) Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 4(3):236–248

    Article  PubMed  CAS  Google Scholar 

  236. Semenova EA, Marchand C, Pommier Y (2008) HIV-1 integrase inhibitors: update and perspectives. Adv Pharmacol 56:199–228

    Article  PubMed  CAS  Google Scholar 

  237. Ceccherini-Silberstein F, Malet I, D’Arrigo R, Antinori A, Marcelin AG, Perno CF (2009) Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev 11(1):17–29

    PubMed  Google Scholar 

  238. Rice P, Craigie R, Davies DR (1996) Retroviral integrases and their cousins. Curr Opin Struct Biol 6(1):76–83

    Article  PubMed  CAS  Google Scholar 

  239. Polard P, Chandler M (1995) Bacterial transposases and retroviral integrases. Mol Microbiol 15(1):13–23

    Article  PubMed  CAS  Google Scholar 

  240. Avidan O, Hizi A (2008) Expression and characterization of the integrase of bovine immunodeficiency virus. Virology 371(2):309–321

    Article  PubMed  CAS  Google Scholar 

  241. Kulkosky J, Katz RA, Merkel G, Skalka AM (1995) Activities and substrate specificity of the evolutionarily conserved central domain of retroviral integrase. Virology 206(1):448–456

    Article  PubMed  CAS  Google Scholar 

  242. Wang JY, Ling H, Yang W, Craigie R (2001) Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. EMBO J 20(24):7333–7343

    Article  PubMed  CAS  Google Scholar 

  243. Chen JC, Krucinski J, Miercke LJ, Finer-Moore JS, Tang AH, Leavitt AD, Stroud RM (2000) Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc Natl Acad Sci USA 97(15):8233–8238

    Article  PubMed  CAS  Google Scholar 

  244. Eijkelenboom AP, Lutzke RA, Boelens R, Plasterk RH, Kaptein R, Hard K (1995) The DNA-binding domain of HIV-1 integrase has an SH3-like fold. Nat Struct Biol 2(9):807–810

    Article  PubMed  CAS  Google Scholar 

  245. Eijkelenboom AP, van den Ent FM, Vos A, Doreleijers JF, Hard K, Tullius TD, Plasterk RH, Kaptein R, Boelens R (1997) The solution structure of the amino-terminal HHCC domain of HIV-2 integrase: a three-helix bundle stabilized by zinc. Curr Biol 7(10):739–746

    Article  PubMed  CAS  Google Scholar 

  246. Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM (1995) Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry 34(31):9826–9833

    Article  PubMed  CAS  Google Scholar 

  247. Cai M, Zheng R, Caffrey M, Craigie R, Clore GM, Gronenborn AM (1997) Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. Nat Struct Biol 4(7):567–577

    Article  PubMed  CAS  Google Scholar 

  248. Wei P, Garber ME, Fang SM, Fischer WH, Jones KA (1998) A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92(4):451–462

    Article  PubMed  CAS  Google Scholar 

  249. D’Orso I, Frankel AD (2010) RNA-mediated displacement of an inhibitory snRNP complex activates transcription elongation. Nat Struct Mol Biol 17(7):815–821

    Article  PubMed  CAS  Google Scholar 

  250. Sobhian B, Laguette N, Yatim A, Nakamura M, Levy Y, Kiernan R, Benkirane M (2010) HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Molecular Cell 38(3):439–451

    Article  PubMed  CAS  Google Scholar 

  251. Barboric M, Lenasi T (2010) Kick-sTARting HIV-1 transcription elongation by 7SK snRNP deporTATion. Nat Struct Mol Biol 17(8):928–930

    Article  PubMed  CAS  Google Scholar 

  252. He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q (2010) HIV-1 tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Molecular Cell 38(3):428–438

    Article  PubMed  CAS  Google Scholar 

  253. Schulte A, Czudnochowski N, Barboric M, Schonichen A, Blazek D, Peterlin BM, Geyer M (2005) Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. J Biol Chem 280(26):24968–24977

    Article  PubMed  CAS  Google Scholar 

  254. Tahirov TH, Babayeva ND, Varzavand K, Cooper JJ, Sedore SC, Price DH (2010) Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 465(7299):747–751

    Article  PubMed  CAS  Google Scholar 

  255. Bannwarth S, Gatignol A (2005) HIV-1 TAR RNA: the target of molecular interactions between the virus and its host. Curr HIV Res 3(1):61–71

    Article  PubMed  CAS  Google Scholar 

  256. Mujtaba S, He Y, Zeng L, Farooq A, Carlson JE, Ott M, Verdin E, Zhou MM (2002) Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Molecular Cell 9(3):575–586

    Article  PubMed  CAS  Google Scholar 

  257. Shojania S, O’Neil JD (2010) Intrinsic disorder and function of the HIV-1 Tat protein. Protein Pept Lett 17(8):999–1011

    Article  PubMed  CAS  Google Scholar 

  258. Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F (1990) Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature 345(6270):84–86

    Article  PubMed  CAS  Google Scholar 

  259. Albini A, Soldi R, Giunciuglio D, Giraudo E, Benelli R, Primo L, Noonan D, Salio M, Camussi G, Rockl W, Bussolino F (1996) The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat Med 2(12):1371–1375

    Article  PubMed  CAS  Google Scholar 

  260. Albini A, Benelli R, Presta M, Rusnati M, Ziche M, Rubartelli A, Paglialunga G, Bussolino F, Noonan D (1996) HIV-tat protein is a heparin-binding angiogenic growth factor. Oncogene 12(2):289–297

    PubMed  CAS  Google Scholar 

  261. Goldstein G (1996) HIV-1 Tat protein as a potential AIDS vaccine. Nat Med 2(9):960–964

    Article  PubMed  CAS  Google Scholar 

  262. Nath A, Psooy K, Martin C, Knudsen B, Magnuson DS, Haughey N, Geiger JD (1996) Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic. J Virol 70(3):1475–1480

    PubMed  CAS  Google Scholar 

  263. Pocernich CB, Sultana R, Mohmmad-Abdul H, Nath A, Butterfield DA (2005) HIV-dementia, Tat-induced oxidative stress, and antioxidant therapeutic considerations. Brain Res Rev 50(1):14–26

    Article  PubMed  CAS  Google Scholar 

  264. András IE, Pu H, Deli MA, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res 74(2):255–265

    Article  PubMed  CAS  Google Scholar 

  265. Banks WA, Robinson SM, Nath A (2005) Permeability of the blood-brain barrier to HIV-1 Tat. Exp Neurol 193(1):218–227

    Article  PubMed  CAS  Google Scholar 

  266. Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Droge W, Lehmann V (1995) HIV-1 Tat potentiates TNF-induced NF-kappaB activation and cytotoxicity by altering the cellular redox state. EMBO J 14(3):546–554

    PubMed  CAS  Google Scholar 

  267. Pumfery A, Deng L, Maddukuri A, de la Fuente C, Li H, Wade JD, Lambert P, Kumar A, Kashanchi F (2003) Chromatin remodeling and modification during HIV-1 Tat-activated transcription. Curr HIV Res 1(3):343–362

    Article  PubMed  CAS  Google Scholar 

  268. Guo X, Kameoka M, Wei X, Roques B, Gotte M, Liang C, Wainberg MA (2003) Suppression of an intrinsic strand transfer activity of HIV-1 Tat protein by its second-exon sequences. Virology 307(1):154–163

    Article  PubMed  CAS  Google Scholar 

  269. Chiu Y-L, Ho CK, Saha N, Schwer B, Shuman S, Rana TM (2002) Tat stimulates cotranscriptional capping of HIV mRNA. Molecular Cell 10(3):585–597

    Article  PubMed  CAS  Google Scholar 

  270. Bennasser Y, Jeang K (2006) HIV-1 Tat interaction with Dicer: requirement for RNA. Retrovirology 3:95–101

    Article  PubMed  CAS  Google Scholar 

  271. Kuciak M, Gabus C, Ivanyi-Nagy R, Semrad K, Storchak R, Chaloin O, Muller S, Mely Y, Darlix J-L (2008) The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro. Nucleic Acids Res 36(10):3389–3400

    Article  PubMed  CAS  Google Scholar 

  272. Gautier V, Gu L, O’Donoghue N, Pennington S, Sheehy N, Hall W (2009) In vitro nuclear interactome of the HIV-1 Tat protein. Retrovirology 6(1):47

    Article  PubMed  CAS  Google Scholar 

  273. Liang C, Wainberg MA (2002) The role of Tat in HIV-1 replication: an activator and/or a suppressor? AIDS Reviews 4(1):41–49

    PubMed  Google Scholar 

  274. Derse D, Carvalho M, Carroll R, Peterlin BM (1991) A minimal lentivirus Tat. J Virol 65(12):7012–7015

    PubMed  CAS  Google Scholar 

  275. Vendel AC, Lumb KJ (2003) Molecular recognition of the human coactivator CBP by the HIV-1 transcriptional activator Tat. Biochemistry 42(4):910–916

    Article  PubMed  CAS  Google Scholar 

  276. Bieniasz PD, Grdina TA, Bogerd HP, Cullen BR (1998) Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat. EMBO J 17(23):7056–7065

    Article  PubMed  CAS  Google Scholar 

  277. Chen D, Wang M, Zhou S, Zhou Q (2002) HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 21(24):6801–6810

    Article  PubMed  CAS  Google Scholar 

  278. Weeks KM, Ampe C, Schultz SC, Steitz TA, Crothers DM (1990) Fragments of the HIV-1 Tat protein specifically bind TAR RNA. Science 249(4974):1281–1285

    Article  PubMed  CAS  Google Scholar 

  279. Anand K, Schulte A, Vogel-Bachmayr K, Scheffzek K, Geyer M (2008) Structural insights into the Cyclin T1-Tat-TAR RNA transcription activation complex from EIAV. Nat Struct Mol Biol 15(12):1287–1292

    Article  PubMed  CAS  Google Scholar 

  280. Gupta B, Levchenko TS, Torchilin VP (2005) Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides. Advan Drug Deliv Rev 57(4):637–651

    Article  CAS  Google Scholar 

  281. Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP (2004) The glutamine-rich region of the HIV-1 Tat protein is involved in T cell apoptosis. J Biol Chem 279(46):48197–48204

    Article  PubMed  CAS  Google Scholar 

  282. Avraham HK, Jiang S, Lee T-H, Prakash O, Avraham S (2004) HIV-1 tat-mediated effects on focal adhesion assembly and permeability in brain microvascular endothelial cells. J Immunol 173(10):6228–6233

    PubMed  CAS  Google Scholar 

  283. Weissman JD, Brown JA, Howcroft TK, Hwang J, Chawla A, Roche PA, Schiltz L, Nakatani Y, Singer DS (1998) HIV-1 Tat binds TAFII250 and represses TAFII250-dependent transcription of major histocompatibility class I genes. Proc Natl Acad Sci USA 95(20):11601–11606

    Article  PubMed  CAS  Google Scholar 

  284. Carroll IR, Wang J, Howcroft TK, Singer DS (1998) HIV Tat represses transcription of the beta2-microglobulin promoter. Mol Immunol 35(18):1171–1178

    Article  PubMed  CAS  Google Scholar 

  285. Howcroft T, Strebel K, Martin M, Singer D (1993) Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260(5112):1320–1322

    Article  PubMed  CAS  Google Scholar 

  286. Lopez-Huertas MR, Callejas S, Abia D, Mateos E, Dopazo A, Alcami J, Coiras M (2010) Modifications in host cell cytoskeleton structure and function mediated by intracellular HIV-1 Tat protein are greatly dependent on the second coding exon. Nucleic Acids Res 38(10):3287–3307

    Article  PubMed  CAS  Google Scholar 

  287. Goh G, Dunker AK, Uversky V (2008) Protein intrinsic disorder toolbox for comparative analysis of viral proteins. BMC Genomics 9(Suppl 2):S4

    Article  PubMed  Google Scholar 

  288. Anand K, Schulte A, Fujinaga K, Scheffzek K, Geyer M (2007) Cyclin box structure of the P-TEFb subunit cyclin T1 derived from a fusion complex with EIAV tat. J Mol Biol 370(5):826–836

    Article  PubMed  CAS  Google Scholar 

  289. Bayer P, Kraft M, Ejchart A, Westendorp M, Frank R, Rosch P (1995) Structural studies of HIV-1 Tat protein. J Mol Biol 247(4):529–535

    PubMed  CAS  Google Scholar 

  290. Uversky VN (2011) Intrinsically disordered proteins may escape unwanted interactions via functional misfolding. Biochim Biophys Acta 1814(5):693–712

    Google Scholar 

  291. Shojania S, O’Neil JD (2006) HIV-1 Tat is a natively unfolded protein: the solution conformation and dynamics of reduced HIV-1 Tat-(1–72) by NMR spectroscopy. J Biol Chem 281(13):8347–8356

    Article  PubMed  CAS  Google Scholar 

  292. Foucault M, Mayol K, Receveur-Bréchot V, Bussat MC, Klinguer-Hamour C, Verrier B, Beck A, Haser R, Gouet P, Guillon C (2010) UV and X-ray structural studies of a 101-residue long Tat protein from a HIV-1 primary isolate and of its mutated, detoxified, vaccine candidate. Proteins Struct Funct Bioinform 78(6):1441–1456

    CAS  Google Scholar 

  293. Cullen BR (2003) Nuclear mRNA export: insights from virology. Trends Biochem Sci 28(8):419–424

    Article  PubMed  CAS  Google Scholar 

  294. Cullen BR (2003) Nuclear RNA export. J Cell Sci 116(Pt 4):587–597

    Article  PubMed  Google Scholar 

  295. Pollard VW, Malim MH (1998) The HIV-1 Rev protein. Annu Rev Microbiol 52:491–532

    Article  PubMed  CAS  Google Scholar 

  296. Ho JH, Kallstrom G, Johnson AW (2000) Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit. J Cell Biol 151(5):1057–1066

    Article  PubMed  CAS  Google Scholar 

  297. Gadal O, Strauss D, Kessl J, Trumpower B, Tollervey D, Hurt E (2001) Nuclear export of 60 s ribosomal subunits depends on Xpo1p and requires a nuclear export sequence-containing factor, Nmd3p, that associates with the large subunit protein Rpl10p. Mol Cell Biol 21(10):3405–3415

    Article  PubMed  CAS  Google Scholar 

  298. Moy TI, Silver PA (2002) Requirements for the nuclear export of the small ribosomal subunit. J Cell Sci 115(Pt 14):2985–2995

    PubMed  CAS  Google Scholar 

  299. Thomas F, Kutay U (2003) Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway. J Cell Sci 116(Pt 12):2409–2419

    Article  PubMed  CAS  Google Scholar 

  300. Fornerod M, Ohno M, Yoshida M, Mattaj IW (1997) CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90(6):1051–1060

    Article  PubMed  CAS  Google Scholar 

  301. Kutay U, Bischoff FR, Kostka S, Kraft R, Gorlich D (1997) Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 90(6):1061–1071

    Article  PubMed  CAS  Google Scholar 

  302. Kutay U, Guttinger S (2005) Leucine-rich nuclear-export signals: born to be weak. Trends Cell Biol 15(3):121–124

    Article  PubMed  CAS  Google Scholar 

  303. Daugherty MD, D’Orso I, Frankel AD (2008) A solution to limited genomic capacity: using adaptable binding surfaces to assemble the functional HIV Rev oligomer on RNA. Mol Cell 31(6):824–834

    Article  PubMed  CAS  Google Scholar 

  304. Auer M, Gremlich HU, Seifert JM, Daly TJ, Parslow TG, Casari G, Gstach H (1994) Helix-loop-helix motif in HIV-1 Rev. Biochemistry 33(10):2988–2996

    Article  PubMed  CAS  Google Scholar 

  305. Thomas SL, Hauber J, Casari G (1997) Probing the structure of the HIV-1 Rev trans-activator protein by functional analysis. Protein Eng 10(2):103–107

    Article  PubMed  CAS  Google Scholar 

  306. Daugherty MD, Liu B, Frankel AD (2010) Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat Struct Mol Biol 17(11):1337–1342

    Article  PubMed  CAS  Google Scholar 

  307. Daugherty MD, Booth DS, Jayaraman B, Cheng Y, Frankel AD (2010) HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes. Proc Natl Acad Sci USA 107(28):12481–12486

    Article  PubMed  CAS  Google Scholar 

  308. Battiste JL, Mao H, Rao NS, Tan R, Muhandiram DR, Kay LE, Frankel AD, Williamson JR (1996) Alpha helix-RNA major groove recognition in an HIV-1 rev peptide-RRE RNA complex. Science 273(5281):1547–1551

    Article  PubMed  CAS  Google Scholar 

  309. Ye X, Gorin A, Ellington AD, Patel DJ (1996) Deep penetration of an alpha-helix into a widened RNA major groove in the HIV-1 rev peptide-RNA aptamer complex. Nat Struct Biol 3(12):1026–1033

    Article  PubMed  CAS  Google Scholar 

  310. Scanlon MJ, Fairlie DP, Craik DJ, Englebretsen DR, West ML (1995) NMR solution structure of the RNA-binding peptide from human immunodeficiency virus (type 1) Rev. Biochemistry 34(26):8242–8249

    Article  PubMed  CAS  Google Scholar 

  311. Guttler T, Madl T, Neumann P, Deichsel D, Corsini L, Monecke T, Ficner R, Sattler M, Gorlich D (2010) NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. Nat Struct Mol Biol 17(11):1367–1376

    Article  PubMed  CAS  Google Scholar 

  312. Cook A, Bono F, Jinek M, Conti E (2007) Structural biology of nucleocytoplasmic transport. Annu Rev Biochem 76:647–671

    Article  PubMed  CAS  Google Scholar 

  313. Anderson JL, Hope TJ (2004) HIV accessory proteins and surviving the host cell. Curr HIV/AIDS Rep 1(1):47–53

    Article  PubMed  Google Scholar 

  314. Malim MH, Emerman M (2008) HIV-1 accessory proteins–ensuring viral survival in a hostile environment. Cell Host Microbe 3(6):388–398

    Article  PubMed  CAS  Google Scholar 

  315. Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, Lawson VA, Crowe S, Maerz A, Sonza S, Learmont J, Sullivan JS, Cunningham A, Dwyer D, Dowton D, Mills J (1995) Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270(5238):988–991

    Article  PubMed  CAS  Google Scholar 

  316. Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC (1995) Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 332(4):228–232

    Article  PubMed  CAS  Google Scholar 

  317. 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(6):1561–1566

    Article  PubMed  CAS  Google Scholar 

  318. Dyer WB, Ogg GS, Demoitie MA, Jin X, Geczy AF, Rowland-Jones SL, McMichael AJ, Nixon DF, Sullivan JS (1999) Strong human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1. J Virol 73(1):436–443

    PubMed  CAS  Google Scholar 

  319. Little SJ, Riggs NL, Chowers MY, Fitch NJ, Richman DD, Spina CA, Guatelli JC (1994) Cell surface CD4 downregulation and resistance to superinfection induced by a defective provirus of HIV-1. Virology 205(2):578–582

    Article  PubMed  CAS  Google Scholar 

  320. Mangasarian A, Foti M, Aiken C, Chin D, Carpentier JL, Trono D (1997) The HIV-1 Nef protein acts as a connector with sorting pathways in the Golgi and at the plasma membrane. Immunity 6(1):67–77

    Article  PubMed  CAS  Google Scholar 

  321. Mangasarian A, Trono D (1997) The multifaceted role of HIV Nef. Res Virol 148(1):30–33

    Article  PubMed  CAS  Google Scholar 

  322. 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(6665):397–401

    Article  PubMed  CAS  Google Scholar 

  323. Geyer M, Peterlin BM (2001) Domain assembly, surface accessibility and sequence conservation in full length HIV-1 Nef. FEBS Lett 496(2–3):91–95

    Article  PubMed  CAS  Google Scholar 

  324. Baugh LL, Garcia JV, Foster JL (2008) Functional characterization of the human immunodeficiency virus type 1 Nef acidic domain. J Virol 82(19):9657–9667

    Article  PubMed  CAS  Google Scholar 

  325. Gerlach H, Laumann V, Martens S, Becker CF, Goody RS, Geyer M (2010) HIV-1 Nef membrane association depends on charge, curvature, composition and sequence. Nat Chem Biol 6(1):46–53

    Article  PubMed  CAS  Google Scholar 

  326. Giese SI, Woerz I, Homann S, Tibroni N, Geyer M, Fackler OT (2006) Specific and distinct determinants mediate membrane binding and lipid raft incorporation of HIV-1(SF2) Nef. Virology 355(2):175–191

    Article  PubMed  CAS  Google Scholar 

  327. Fackler OT, Moris A, Tibroni N, Giese SI, Glass B, Schwartz O, Krausslich HG (2006) Functional characterization of HIV-1 Nef mutants in the context of viral infection. Virology 351(2):322–339

    Article  PubMed  CAS  Google Scholar 

  328. Bentham M, Mazaleyrat S, Harris M (2006) Role of myristoylation and N-terminal basic residues in membrane association of the human immunodeficiency virus type 1 Nef protein. J Gen Virol 87(Pt 3):563–571

    Article  PubMed  CAS  Google Scholar 

  329. Swingler S, Mann A, Jacque J, Brichacek B, Sasseville VG, Williams K, Lackner AA, Janoff EN, Wang R, Fisher D, Stevenson M (1999) HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat Med 5(9):997–1003

    Article  PubMed  CAS  Google Scholar 

  330. Messmer D, Jacque JM, Santisteban C, Bristow C, Han SY, Villamide-Herrera L, Mehlhop E, Marx PA, Steinman RM, Gettie A, Pope M (2002) Endogenously expressed nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells. J Immunol 169(8):4172–4182

    PubMed  CAS  Google Scholar 

  331. Dai L, Stevenson M (2010) A novel motif in HIV-1 Nef that regulates MIP-1beta chemokine release in macrophages. J Virol 84(16):8327–8331

    Article  PubMed  CAS  Google Scholar 

  332. Lee CH, Leung B, Lemmon MA, Zheng J, Cowburn D, Kuriyan J, Saksela K (1995) A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein. EMBO J 14(20):5006–5015

    PubMed  CAS  Google Scholar 

  333. Renkema GH, Manninen A, Mann DA, Harris M, Saksela K (1999) Identification of the Nef-associated kinase as p21-activated kinase 2. Curr Biol 9(23):1407–1410

    Article  PubMed  CAS  Google Scholar 

  334. Fackler OT, Luo W, Geyer M, Alberts AS, Peterlin BM (1999) Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol Cell 3(6):729–739

    Article  PubMed  CAS  Google Scholar 

  335. Greenway A, McPhee D (1997) HIV1 Nef: the Machiavelli of cellular activation. Res Virol 148(1):58–64

    Article  PubMed  CAS  Google Scholar 

  336. Moarefi I, LaFevre-Bernt M, Sicheri F, Huse M, Lee CH, Kuriyan J, Miller WT (1997) Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature 385(6617):650–653

    Article  PubMed  CAS  Google Scholar 

  337. Benichou S, Liu LX, Erdtmann L, Selig L, Benarous R (1997) Use of the two-hybrid system to identify cellular partners of the HIV1 Nef protein. Res Virol 148(1):71–73

    Article  PubMed  CAS  Google Scholar 

  338. Lee CH, Saksela K, Mirza UA, Chait BT, Kuriyan J (1996) Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain. Cell 85(6):931–942

    Article  PubMed  CAS  Google Scholar 

  339. Sawai ET, Cheng-Mayer C, Luciw PA (1997) Nef and the Nef-associated kinase. Res Virol 148(1):47–52

    Article  PubMed  CAS  Google Scholar 

  340. Costa LJ, Chen N, Lopes A, Aguiar RS, Tanuri A, Plemenitas A, Peterlin BM (2006) Interactions between Nef and AIP1 proliferate multivesicular bodies and facilitate egress of HIV-1. Retrovirology 3:33

    Article  PubMed  CAS  Google Scholar 

  341. Poe JA, Smithgall TE (2009) HIV-1 Nef dimerization is required for Nef-mediated receptor downregulation and viral replication. J Mol Biol 394(2):329–342

    Article  PubMed  CAS  Google Scholar 

  342. Freund J, Kellner R, Houthaeve T, Kalbitzer HR (1994) Stability and proteolytic domains of Nef protein from human immunodeficiency virus (HIV) type 1. Eur J Biochem 221(2):811–819

    Article  PubMed  CAS  Google Scholar 

  343. Grzesiek S, Bax A, Hu JS, Kaufman J, Palmer I, Stahl SJ, Tjandra N, Wingfield PT (1997) Refined solution structure and backbone dynamics of HIV-1 Nef. Protein Sci 6(6):1248–1263

    Article  PubMed  CAS  Google Scholar 

  344. Geyer M, Munte CE, Schorr J, Kellner R, Kalbitzer HR (1999) Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef protein. J Mol Biol 289(1):123–138

    Article  PubMed  CAS  Google Scholar 

  345. Sodroski J, Goh WC, Rosen C, Tartar A, Portetelle D, Burny A, Haseltine W (1986) Replicative and cytopathic potential of HTLV-III/LAV with sor gene deletions. Science 231(4745):1549–1553

    Article  PubMed  CAS  Google Scholar 

  346. Strebel K, Daugherty D, Clouse K, Cohen D, Folks T, Martin MA (1987) The HIV ‘A’ (sor) gene product is essential for virus infectivity. Nature 328(6132):728–730

    Article  PubMed  CAS  Google Scholar 

  347. Gabuzda DH, Lawrence K, Langhoff E, Terwilliger E, Dorfman T, Haseltine WA, Sodroski J (1992) Role of vif in replication of human immunodeficiency virus type 1 in CD4 + T lymphocytes. J Virol 66(11):6489–6495

    PubMed  CAS  Google Scholar 

  348. Borman AM, Quillent C, Charneau P, Dauguet C, Clavel F (1995) Human immunodeficiency virus type 1 Vif- mutant particles from restrictive cells: role of Vif in correct particle assembly and infectivity. J Virol 69(4):2058–2067

    PubMed  CAS  Google Scholar 

  349. Courcoul M, Patience C, Rey F, Blanc D, Harmache A, Sire J, Vigne R, Spire B (1995) Peripheral blood mononuclear cells produce normal amounts of defective Vif- human immunodeficiency virus type 1 particles which are restricted for the preretrotranscription steps. J Virol 69(4):2068–2074

    PubMed  CAS  Google Scholar 

  350. Strebel K (2007) HIV accessory genes Vif and Vpu. Adv Pharmacol 55:199–232

    Article  PubMed  CAS  Google Scholar 

  351. Sheehy AM, Gaddis NC, Choi JD, Malim MH (2002) Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418(6898):646–650

    Article  PubMed  CAS  Google Scholar 

  352. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (2003) DNA deamination mediates innate immunity to retroviral infection. Cell 113(6):803–809

    Article  PubMed  CAS  Google Scholar 

  353. Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (2003) Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424(6944):99–103

    Article  PubMed  CAS  Google Scholar 

  354. Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L (2003) The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 424(6944):94–98

    Article  PubMed  CAS  Google Scholar 

  355. Yang B, Chen K, Zhang C, Huang S, Zhang H (2007) Virion-associated uracil DNA glycosylase-2 and apurinic/apyrimidinic endonuclease are involved in the degradation of APOBEC3G-edited nascent HIV-1 DNA. J Biol Chem 282(16):11667–11675

    Article  PubMed  CAS  Google Scholar 

  356. Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K (2003) The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. J Virol 77(21):11398–11407

    Article  PubMed  CAS  Google Scholar 

  357. Kremer M, Schnierle BS (2005) HIV-1 Vif: HIV’s weapon against the cellular defense factor APOBEC3G. Curr HIV Res 3(4):339–344

    Article  PubMed  CAS  Google Scholar 

  358. Mehle A, Strack B, Ancuta P, Zhang C, McPike M, Gabuzda D (2004) Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway. J Biol Chem 279(9):7792–7798

    Article  PubMed  CAS  Google Scholar 

  359. Wedekind JE, Dance GS, Sowden MP, Smith HC (2003) Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet 19(4):207–216

    Article  PubMed  CAS  Google Scholar 

  360. Wissing S, Galloway NL, Greene WC (2010) HIV-1 Vif versus the APOBEC3 cytidine deaminases: an intracellular duel between pathogen and host restriction factors. Mol Aspects Med 31:383–397

    Article  PubMed  CAS  Google Scholar 

  361. Marin M, Rose KM, Kozak SL, Kabat D (2003) HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nat Med 9(11):1398–1403

    Article  PubMed  CAS  Google Scholar 

  362. 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(5647):1056–1060

    Article  PubMed  CAS  Google Scholar 

  363. Shirakawa K, Takaori-Kondo A, Kobayashi M, Tomonaga M, Izumi T, Fukunaga K, Sasada A, Abudu A, Miyauchi Y, Akari H, Iwai K, Uchiyama T (2005) Ubiquitination of APOBEC3 proteins by the Vif-Cullin5-ElonginB-ElonginC complex. Virology 344(2):263–266

    Article  PubMed  CAS  Google Scholar 

  364. Miller JH, Presnyak V, Smith HC (2007) The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G. Retrovirology 4:81

    Article  PubMed  CAS  Google Scholar 

  365. Yamashita T, Nomaguchi M, Miyake A, Uchiyama T, Adachi A (2010) Status of APOBEC3G/F in cells and progeny virions modulated by Vif determines HIV-1 infectivity. Microbes Infect 12(2):166–171

    Article  PubMed  CAS  Google Scholar 

  366. Santa-Marta M, da Silva FA, Fonseca AM, Goncalves J (2005) HIV-1 Vif can directly inhibit apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G-mediated cytidine deamination by using a single amino acid interaction and without protein degradation. J Biol Chem 280(10):8765–8775

    Article  PubMed  CAS  Google Scholar 

  367. Santa-Marta M, Aires da Silva F, Fonseca AM, Rato S, Goncalves J (2007) HIV-1 Vif protein blocks the cytidine deaminase activity of B-cell specific AID in E. coli by a similar mechanism of action. Mol Immunol 44(4):583–590

    Article  PubMed  CAS  Google Scholar 

  368. Stopak K, de Noronha C, Yonemoto W, Greene WC (2003) HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol Cell 12(3):591–601

    Article  PubMed  CAS  Google Scholar 

  369. Mercenne G, Bernacchi S, Richer D, Bec G, Henriet S, Paillart JC, Marquet R (2010) HIV-1 Vif binds to APOBEC3G mRNA and inhibits its translation. Nucleic Acids Res 38(2):633–646

    Article  PubMed  CAS  Google Scholar 

  370. Simon JH, Miller DL, Fouchier RA, Malim MH (1998) Virion incorporation of human immunodeficiency virus type-1 Vif is determined by intracellular expression level and may not be necessary for function. Virology 248(2):182–187

    Article  PubMed  CAS  Google Scholar 

  371. Kao S, Akari H, Khan MA, Dettenhofer M, Yu XF, Strebel K (2003) Human immunodeficiency virus type 1 Vif is efficiently packaged into virions during productive but not chronic infection. J Virol 77(2):1131–1140

    Article  PubMed  CAS  Google Scholar 

  372. Khan MA, Aberham C, Kao S, Akari H, Gorelick R, Bour S, Strebel K (2001) Human immunodeficiency virus type 1 Vif protein is packaged into the nucleoprotein complex through an interaction with viral genomic RNA. J Virol 75(16):7252–7265

    Article  PubMed  CAS  Google Scholar 

  373. Goncalves J, Jallepalli P, Gabuzda DH (1994) Subcellular localization of the Vif protein of human immunodeficiency virus type 1. J Virol 68(2):704–712

    PubMed  CAS  Google Scholar 

  374. Goncalves J, Shi B, Yang X, Gabuzda D (1995) Biological activity of human immunodeficiency virus type 1 Vif requires membrane targeting by C-terminal basic domains. J Virol 69(11):7196–7204

    PubMed  CAS  Google Scholar 

  375. Simon JH, Fouchier RA, Southerling TE, Guerra CB, Grant CK, Malim MH (1997) The Vif and Gag proteins of human immunodeficiency virus type 1 colocalize in infected human T cells. J Virol 71(7):5259–5267

    PubMed  CAS  Google Scholar 

  376. Auclair JR, Green KM, Shandilya S, Evans JE, Somasundaran M, Schiffer CA (2007) Mass spectrometry analysis of HIV-1 Vif reveals an increase in ordered structure upon oligomerization in regions necessary for viral infectivity. Proteins 69(2):270–284

    Article  PubMed  CAS  Google Scholar 

  377. Yang B, Gao L, Li L, Lu Z, Fan X, Patel CA, Pomerantz RJ, DuBois GC, Zhang H (2003) Potent suppression of viral infectivity by the peptides that inhibit multimerization of human immunodeficiency virus type 1 (HIV-1) Vif proteins. J Biol Chem 278(8):6596–6602

    Article  PubMed  CAS  Google Scholar 

  378. Yang S, Sun Y, Zhang H (2001) The multimerization of human immunodeficiency virus type I Vif protein: a requirement for Vif function in the viral life cycle. J Biol Chem 276(7):4889–4893

    Article  PubMed  CAS  Google Scholar 

  379. Yang X, Goncalves J, Gabuzda D (1996) Phosphorylation of Vif and its role in HIV-1 replication. J Biol Chem 271(17):10121–10129

    Article  PubMed  CAS  Google Scholar 

  380. Mehle A, Goncalves J, Santa-Marta M, McPike M, Gabuzda D (2004) Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation. Genes Dev 18(23):2861–2866

    Article  PubMed  CAS  Google Scholar 

  381. Yang X, Gabuzda D (1998) Mitogen-activated protein kinase phosphorylates and regulates the HIV-1 Vif protein. J Biol Chem 273(45):29879–29887

    Article  PubMed  CAS  Google Scholar 

  382. Khan MA, Akari H, Kao S, Aberham C, Davis D, Buckler-White A, Strebel K (2002) Intravirion processing of the human immunodeficiency virus type 1 Vif protein by the viral protease may be correlated with Vif function. J Virol 76(18):9112–9123

    Article  PubMed  CAS  Google Scholar 

  383. Tian C, Yu X, Zhang W, Wang T, Xu R, Yu XF (2006) Differential requirement for conserved tryptophans in human immunodeficiency virus type 1 Vif for the selective suppression of APOBEC3G and APOBEC3F. J Virol 80(6):3112–3115

    Article  PubMed  CAS  Google Scholar 

  384. Simon V, Zennou V, Murray D, Huang Y, Ho DD, Bieniasz PD (2005) Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathog 1(1):e6

    Article  PubMed  CAS  Google Scholar 

  385. Dang Y, Davis RW, York IA, Zheng YH (2010) Identification of 81LGxGxxIxW89 and 171EDRW174 domains from human immunodeficiency virus type 1 Vif that regulate APOBEC3G and APOBEC3F neutralizing activity. J Virol 84(11):5741–5750

    Article  PubMed  CAS  Google Scholar 

  386. Dang Y, Wang X, Zhou T, York IA, Zheng YH (2009) Identification of a novel WxSLVK motif in the N terminus of human immunodeficiency virus and simian immunodeficiency virus Vif that is critical for APOBEC3G and APOBEC3F neutralization. J Virol 83(17):8544–8552

    Article  PubMed  CAS  Google Scholar 

  387. Chen G, He Z, Wang T, Xu R, Yu XF (2009) A patch of positively charged amino acids surrounding the human immunodeficiency virus type 1 Vif SLVx4Yx9Y motif influences its interaction with APOBEC3G. J Virol 83(17):8674–8682

    Article  PubMed  CAS  Google Scholar 

  388. Henriet S, Sinck L, Bec G, Gorelick RJ, Marquet R, Paillart JC (2007) Vif is a RNA chaperone that could temporally regulate RNA dimerization and the early steps of HIV-1 reverse transcription. Nucleic Acids Res 35(15):5141–5153

    Article  PubMed  CAS  Google Scholar 

  389. Henriet S, Richer D, Bernacchi S, Decroly E, Vigne R, Ehresmann B, Ehresmann C, Paillart JC, Marquet R (2005) Cooperative and specific binding of Vif to the 5′ region of HIV-1 genomic RNA. J Mol Biol 354(1):55–72

    Article  PubMed  CAS  Google Scholar 

  390. Bernacchi S, Henriet S, Dumas P, Paillart JC, Marquet R (2007) RNA and DNA binding properties of HIV-1 Vif protein: a fluorescence study. J Biol Chem 282(36):26361–26368

    Article  PubMed  CAS  Google Scholar 

  391. Dettenhofer M, Cen S, Carlson BA, Kleiman L, Yu XF (2000) Association of human immunodeficiency virus type 1 Vif with RNA and its role in reverse transcription. J Virol 74(19):8938–8945

    Article  PubMed  CAS  Google Scholar 

  392. Zhang H, Pomerantz RJ, Dornadula G, Sun Y (2000) Human immunodeficiency virus type 1 Vif protein is an integral component of an mRNP complex of viral RNA and could be involved in the viral RNA folding and packaging process. J Virol 74(18):8252–8261

    Article  PubMed  CAS  Google Scholar 

  393. Baraz L, Friedler A, Blumenzweig I, Nussinuv O, Chen N, Steinitz M, Gilon C, Kotler M (1998) Human immunodeficiency virus type 1 Vif-derived peptides inhibit the viral protease and arrest virus production. FEBS Lett 441(3):419–426

    Article  PubMed  CAS  Google Scholar 

  394. Friedler A, Blumenzweig I, Baraz L, Steinitz M, Kotler M, Gilon C (1999) Peptides derived from HIV-1 Vif: a non-substrate based novel type of HIV-1 protease inhibitors. J Mol Biol 287(1):93–101

    Article  PubMed  CAS  Google Scholar 

  395. Baraz L, Hutoran M, Blumenzweig I, Katzenellenbogen M, Friedler A, Gilon C, Steinitz M, Kotler M (2002) Human immunodeficiency virus type 1 Vif binds the viral protease by interaction with its N-terminal region. J Gen Virol 83(Pt 9):2225–2230

    PubMed  CAS  Google Scholar 

  396. Izumi T, Takaori-Kondo A, Shirakawa K, Higashitsuji H, Itoh K, Io K, Matsui M, Iwai K, Kondoh H, Sato T, Tomonaga M, Ikeda S, Akari H, Koyanagi Y, Fujita J, Uchiyama T (2009) MDM2 is a novel E3 ligase for HIV-1 Vif. Retrovirology 6:1

    Article  PubMed  CAS  Google Scholar 

  397. Luo K, Xiao Z, Ehrlich E, Yu Y, Liu B, Zheng S, Yu XF (2005) Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5–E3 ligase through a HCCH motif to suppress APOBEC3G. Proc Natl Acad Sci USA 102(32):11444–11449

    Article  PubMed  CAS  Google Scholar 

  398. Mehle A, Thomas ER, Rajendran KS, Gabuzda D (2006) A zinc-binding region in Vif binds Cul5 and determines cullin selection. J Biol Chem 281(25):17259–17265

    Article  PubMed  CAS  Google Scholar 

  399. Xiao Z, Xiong Y, Zhang W, Tan L, Ehrlich E, Guo D, Yu XF (2007) Characterization of a Novel Cullin5 Binding Domain in HIV-1 Vif. J Mol Biol 373(3):541–550

    Article  PubMed  CAS  Google Scholar 

  400. Oberste MS, Gonda MA (1992) Conservation of amino-acid sequence motifs in lentivirus Vif proteins. Virus Genes 6(1):95–102

    Article  PubMed  CAS  Google Scholar 

  401. Yu Y, Xiao Z, Ehrlich ES, Yu X, Yu XF (2004) Selective assembly of HIV-1 Vif-Cul5-ElonginB-ElonginC E3 ubiquitin ligase complex through a novel SOCS box and upstream cysteines. Genes Dev 18(23):2867–2872

    Article  PubMed  CAS  Google Scholar 

  402. Schmitt K, Hill MS, Ruiz A, Culley N, Pinson DM, Wong SW, Stephens EB (2009) Mutations in the highly conserved SLQYLA motif of Vif in a simian-human immunodeficiency virus result in a less pathogenic virus and are associated with G-to-A mutations in the viral genome. Virology 383(2):362–372

    Article  PubMed  CAS  Google Scholar 

  403. Pomerantz RJ (2003) The HIV-1 Vif protein: a paradigm for viral:cell interactions. Cell Mol Life Sci 60(10):2017–2019

    Article  PubMed  CAS  Google Scholar 

  404. Donahue JP, Vetter ML, Mukhtar NA, D’Aquila RT (2008) The HIV-1 Vif PPLP motif is necessary for human APOBEC3G binding and degradation. Virology 377(1):49–53

    Article  PubMed  CAS  Google Scholar 

  405. Kataropoulou A, Bovolenta C, Belfiore A, Trabatti S, Garbelli A, Porcellini S, Lupo R, Maga G (2009) Mutational analysis of the HIV-1 auxiliary protein Vif identifies independent domains important for the physical and functional interaction with HIV-1 reverse transcriptase. Nucleic Acids Res 37(11):3660–3669

    Article  PubMed  CAS  Google Scholar 

  406. Bergeron JR, Huthoff H, Veselkov DA, Beavil RL, Simpson PJ, Matthews SJ, Malim MH, Sanderson MR (2010) The SOCS-box of HIV-1 Vif interacts with ElonginBC by induced-folding to recruit its Cul5-containing ubiquitin ligase complex. PLoS Pathog 6(6):e1000925

    Article  PubMed  CAS  Google Scholar 

  407. Wolfe LS, Stanley BJ, Liu C, Eliason WK, Xiong Y (2010) Dissection of the HIV Vif interaction with human E3 ubiquitin ligase. J Virol 84(14):7135–7139

    Article  PubMed  CAS  Google Scholar 

  408. Bouyac M, Courcoul M, Bertoia G, Baudat Y, Gabuzda D, Blanc D, Chazal N, Boulanger P, Sire J, Vigne R, Spire B (1997) Human immunodeficiency virus type 1 Vif protein binds to the Pr55Gag precursor. J Virol 71(12):9358–9365

    PubMed  CAS  Google Scholar 

  409. Reingewertz TH, Shalev DE, Friedler A (2010) Structural disorder in the HIV-1 Vif protein and interaction-dependent gain of structure. Protein Pept Lett 17(8):988–998

    Article  PubMed  CAS  Google Scholar 

  410. Combet C, Blanchet C, Geourjon C, Deleage G (2000) NPS@: network protein sequence analysis. Trends Biochem Sci 25(3):147–150

    Article  PubMed  CAS  Google Scholar 

  411. Xiao Z, Ehrlich E, Yu Y, Luo K, Wang T, Tian C, Yu XF (2006) Assembly of HIV-1 Vif-Cul5 E3 ubiquitin ligase through a novel zinc-binding domain-stabilized hydrophobic interface in Vif. Virology 349(2):290–299

    Article  PubMed  CAS  Google Scholar 

  412. Giri K, Scott RA, Maynard EL (2009) Molecular structure and biochemical properties of the HCCH-Zn2 + site in HIV-1 Vif. Biochemistry 48(33):7969–7978

    Article  PubMed  CAS  Google Scholar 

  413. Giri K, Maynard EL (2009) Conformational analysis of a peptide approximating the HCCH motif in HIV-1 Vif. Biopolymers 92(5):417–425

    Article  PubMed  CAS  Google Scholar 

  414. Paul I, Cui J, Maynard EL (2006) Zinc binding to the HCCH motif of HIV-1 virion infectivity factor induces a conformational change that mediates protein–protein interactions. Proc Natl Acad Sci U S A 103(49):18475–18480

    Article  PubMed  CAS  Google Scholar 

  415. Reingewertz TH, Benyamini H, Lebendiker M, Shalev DE, Friedler A (2009) The C-terminal domain of the HIV-1 Vif protein is natively unfolded in its unbound state. Protein Eng Des Sel 22(5):281–287

    Article  PubMed  CAS  Google Scholar 

  416. Bernacchi S, Mercenne G, Tournaire C, Marquet R, Paillart JC (2010) Importance of the proline-rich multimerization domain on the oligomerization and nucleic acid binding properties of HIV-1 Vif. Nucleic Acids Res

  417. Stanley BJ, Ehrlich ES, Short L, Yu Y, Xiao Z, Yu XF, Xiong Y (2008) Structural insight into the human immunodeficiency virus Vif SOCS box and its role in human E3 ubiquitin ligase assembly. J Virol 82(17):8656–8663

    Article  PubMed  CAS  Google Scholar 

  418. Stanley BJ, Ehrlich ES, Short L, Yu Y, Xiao Z, Yu XF, Xiong Y (2008) Structural Insight into the HIV Vif SOCS Box and Its Role in Human E3 Ubiquitin Ligase Assembly. J Virol 82(17):8656–8663

    Article  PubMed  CAS  Google Scholar 

  419. Marcsisin SR, Engen JR (2011) Molecular insight into the conformational dynamics of the elongin bc complex and its interaction with HIV-1 Vif. J Mol Biol 402(5):892–904

    Article  CAS  Google Scholar 

  420. Lu YL, Bennett RP, Wills JW, Gorelick R, Ratner L (1995) A leucine triplet repeat sequence (LXX)4 in p6gag is important for Vpr incorporation into human immunodeficiency virus type 1 particles. J Virol 69(11):6873–6879

    PubMed  CAS  Google Scholar 

  421. Connor RI, Chen BK, Choe S, Landau NR (1995) Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206(2):935–944

    Article  PubMed  CAS  Google Scholar 

  422. Subbramanian RA, Kessous-Elbaz A, Lodge R, Forget J, Yao XJ, Bergeron D, Cohen EA (1998) Human immunodeficiency virus type 1 Vpr is a positive regulator of viral transcription and infectivity in primary human macrophages. J Exp Med 187(7):1103–1111

    Article  PubMed  CAS  Google Scholar 

  423. Miller MD, Farnet CM, Bushman FD (1997) Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol 71(7):5382–5390

    PubMed  CAS  Google Scholar 

  424. Cohen EA, Subbramanian RA, Gottlinger HG (1996) Role of auxiliary proteins in retroviral morphogenesis. Curr Top Microbiol Immunol 214:219–235

    Article  PubMed  CAS  Google Scholar 

  425. Emerman M (1996) HIV-1, Vpr and the cell cycle. Curr Biol 6(9):1096–1103

    Article  PubMed  CAS  Google Scholar 

  426. Tungaturthi PK, Sawaya BE, Singh SP, Tomkowicz B, Ayyavoo V, Khalili K, Collman RG, Amini S, Srinivasan A (2003) Role of HIV-1 Vpr in AIDS pathogenesis: relevance and implications of intravirion, intracellular and free Vpr. Biomed Pharmacother 57(1):20–24

    Article  PubMed  CAS  Google Scholar 

  427. Majumder B, Venkatachari NJ, Srinivasan A, Ayyavoo V (2009) HIV-1 mediated immune pathogenesis: spotlight on the role of viral protein R (Vpr). Curr HIV Res 7(2):169–177

    Article  PubMed  CAS  Google Scholar 

  428. Andersen JL, Planelles V (2005) The role of Vpr in HIV-1 pathogenesis. Curr HIV Res 3(1):43–51

    Article  PubMed  CAS  Google Scholar 

  429. Sawaya BE, Khalili K, Gordon J, Taube R, Amini S (2000) Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome. J Biol Chem 275(45):35209–35214

    Article  PubMed  CAS  Google Scholar 

  430. Chang F, Re F, Sebastian S, Sazer S, Luban J (2004) HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes. Mol Biol Cell 15(4):1793–1801

    Article  PubMed  CAS  Google Scholar 

  431. Rogel ME, Wu LI, Emerman M (1995) The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J Virol 69(2):882–888

    PubMed  CAS  Google Scholar 

  432. Ramanathan MP, Curley E 3rd, Su M, Chambers JA, Weiner DB (2002) Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling. J Biol Chem 277(49):47854–47860

    Article  PubMed  CAS  Google Scholar 

  433. Jowett JB, Xie YM, Chen IS (1999) The presence of human immunodeficiency virus type 1 Vpr correlates with a decrease in the frequency of mutations in a plasmid shuttle vector. J Virol 73(9):7132–7137

    PubMed  CAS  Google Scholar 

  434. Piller SC, Ewart GD, Jans DA, Gage PW, Cox GB (1999) The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons. J Virol 73(5):4230–4238

    PubMed  CAS  Google Scholar 

  435. Somasundaran M, Sharkey M, Brichacek B, Luzuriaga K, Emerman M, Sullivan JL, Stevenson M (2002) Evidence for a cytopathogenicity determinant in HIV-1 Vpr. Proc Natl Acad Sci U S A 99(14):9503–9508

    Article  PubMed  CAS  Google Scholar 

  436. Henklein P, Bruns K, Sherman MP, Tessmer U, Licha K, Kopp J, de Noronha CM, Greene WC, Wray V, Schubert U (2000) Functional and structural characterization of synthetic HIV-1 Vpr that transduces cells, localizes to the nucleus, and induces G2 cell cycle arrest. J Biol Chem 275(41):32016–32026

    Article  PubMed  CAS  Google Scholar 

  437. Morellet N, Bouaziz S, Petitjean P, Roques BP (2003) NMR structure of the HIV-1 regulatory protein VPR. J Mol Biol 327(1):215–227

    Article  PubMed  CAS  Google Scholar 

  438. Wecker K, Morellet N, Bouaziz S, Roques BP (2002) NMR structure of the HIV-1 regulatory protein Vpr in H2O/trifluoroethanol: Comparison with the Vpr N-terminal (1–51) and C-terminal (52–96) domains. Eur J Biochem 269(15):3779–3788

    Article  PubMed  CAS  Google Scholar 

  439. Romani B, Engelbrecht S (2009) Human immunodeficiency virus type 1 Vpr: functions and molecular interactions. J Gen Virol 90(Pt 8):1795–1805

    Article  PubMed  CAS  Google Scholar 

  440. Mahalingam S, Ayyavoo V, Patel M, Kieber-Emmons T, Weiner DB (1997) Nuclear import, virion incorporation, and cell cycle arrest/differentiation are mediated by distinct functional domains of human immunodeficiency virus type 1 Vpr. J Virol 71(9):6339–6347

    PubMed  CAS  Google Scholar 

  441. Mahalingam S, Khan SA, Jabbar MA, Monken CE, Collman RG, Srinivasan A (1995) Identification of residues in the N-terminal acidic domain of HIV-1 Vpr essential for virion incorporation. Virology 207(1):297–302

    Article  PubMed  CAS  Google Scholar 

  442. Mahalingam S, Patel M, Collman RG, Srinivasan A (1995) The carboxy-terminal domain is essential for stability and not for virion incorporation of HIV-1 Vpr into virus particles. Virology 214(2):647–652

    Article  PubMed  CAS  Google Scholar 

  443. Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G (2002) The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway. Cell Death Differ 9(11):1212–1219

    Article  PubMed  CAS  Google Scholar 

  444. Li MS, Garcia-Asua G, Bhattacharyya U, Mascagni P, Austen BM, Roberts MM (1996) The Vpr protein of human immunodeficiency virus type 1 binds to nucleocapsid protein p7 in vitro. Biochem Biophys Res Commun 218(1):352–355

    Article  PubMed  CAS  Google Scholar 

  445. de Rocquigny H, Petitjean P, Tanchou V, Decimo D, Drouot L, Delaunay T, Darlix JL, Roques BP (1997) The zinc fingers of HIV nucleocapsid protein NCp7 direct interactions with the viral regulatory protein Vpr. J Biol Chem 272(49):30753–30759

    Article  PubMed  Google Scholar 

  446. Bourbigot S, Beltz H, Denis J, Morellet N, Roques BP, Mely Y, Bouaziz S (2005) The C-terminal domain of the HIV-1 regulatory protein Vpr adopts an antiparallel dimeric structure in solution via its leucine-zipper-like domain. Biochem J 387(Pt 2):333–341

    PubMed  CAS  Google Scholar 

  447. Basanez G, Zimmerberg J (2001) HIV and apoptosis death and the mitochondrion. J Exp Med 193(4):F11–F14

    Article  PubMed  CAS  Google Scholar 

  448. Patil A, Nakamura H (2006) Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett 580(8):2041–2045

    Article  PubMed  CAS  Google Scholar 

  449. Ekman D, Light S, Bjorklund AK, Elofsson A (2006) What properties characterize the hub proteins of the protein–protein interaction network of Saccharomyces cerevisiae? Genome Biol 7(6):R45

    Article  PubMed  CAS  Google Scholar 

  450. Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2(8):e100

    Article  PubMed  CAS  Google Scholar 

  451. Dosztanyi Z, Chen J, Dunker AK, Simon I, Tompa P (2006) Disorder and sequence repeats in hub proteins and their implications for network evolution. J Proteome Res 5(11):2985–2995

    Article  PubMed  CAS  Google Scholar 

  452. Singh GP, Ganapathi M, Dash D (2007) Role of intrinsic disorder in transient interactions of hub proteins. Proteins 66(4):761–765

    Article  PubMed  CAS  Google Scholar 

  453. Singh GP, Dash D (2007) Intrinsic disorder in yeast transcriptional regulatory network. Proteins 68(3):602–605

    Article  PubMed  CAS  Google Scholar 

  454. Oldfield CJ, Meng J, Yang JY, Yang MQ, Uversky VN, Dunker AK (2008) Flexible nets: disorder and induced fit in the associations of p53 and 14–3-3 with their partners. BMC Genomics 9(Suppl 1):S1

    Article  CAS  Google Scholar 

  455. Cohen EA, Terwilliger EF, Sodroski JG, Haseltine WA (1988) Identification of a protein encoded by the vpu gene of HIV-1. Nature 334(6182):532–534

    Article  PubMed  CAS  Google Scholar 

  456. Strebel K, Klimkait T, Martin MA (1988) A novel gene of HIV-1, vpu, and its 16-kilodalton product. Science 241(4870):1221–1223

    Article  PubMed  CAS  Google Scholar 

  457. Maldarelli F, Chen MY, Willey RL, Strebel K (1993) Human immunodeficiency virus type 1 Vpu protein is an oligomeric type I integral membrane protein. J Virol 67(8):5056–5061

    PubMed  CAS  Google Scholar 

  458. Willey RL, Maldarelli F, Martin MA, Strebel K (1992) Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol 66(12):7193–7200

    PubMed  CAS  Google Scholar 

  459. 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(1):226–234

    PubMed  CAS  Google Scholar 

  460. Chen MY, Maldarelli 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(7):3877–3884

    PubMed  CAS  Google Scholar 

  461. 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(12):7699–7711

    PubMed  CAS  Google Scholar 

  462. 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(3):1510–1520

    PubMed  CAS  Google Scholar 

  463. 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(13):5163–5167

    Article  PubMed  CAS  Google Scholar 

  464. 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 

  465. Ewart GD, Sutherland T, Gage PW, Cox GB (1996) The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels. J Virol 70(10):7108–7115

    PubMed  CAS  Google Scholar 

  466. Schubert U, Ferrer-Montiel AV, Oblatt-Montal M, Henklein P, Strebel K, Montal M (1996) 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(1):12–18

    Article  PubMed  CAS  Google Scholar 

  467. Schubert U, Bour S, Ferrer-Montiel AV, Montal M, Maldarell F, Strebel K (1996) The two biological activities of human immunodeficiency virus type 1 Vpu protein involve two separable structural domains. J Virol 70(2):809–819

    PubMed  CAS  Google Scholar 

  468. 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(25):15154–15159

    Article  PubMed  CAS  Google Scholar 

  469. 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(2):259–267

    Article  PubMed  CAS  Google Scholar 

  470. Hsu K, Han J, Shinlapawittayatorn K, Deschenes I, Marban E (2010) Membrane potential depolarization as a triggering mechanism for Vpu-mediated HIV-1 release. Biophys J 99(6):1718–1725

    Article  PubMed  CAS  Google Scholar 

  471. Neil SJ, Zang T, Bieniasz PD (2008) Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451(7177):425–430

    Article  PubMed  CAS  Google Scholar 

  472. 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(4):245–252

    Article  PubMed  CAS  Google Scholar 

  473. 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(2):381–386

    Article  PubMed  CAS  Google Scholar 

  474. Tiganos E, Yao XJ, Friborg J, Daniel N, Cohen EA (1997) Putative alpha-helical structures in the human immunodeficiency virus type 1 Vpu protein and CD4 are involved in binding and degradation of the CD4 molecule. J Virol 71(6):4452–4460

    PubMed  CAS  Google Scholar 

  475. 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(4):565–574

    Article  PubMed  CAS  Google Scholar 

  476. Bour S, Strebel K (2003) The HIV-1 Vpu protein: a multifunctional enhancer of viral particle release. Microbes Infect 5(11):1029–1039

    Article  PubMed  CAS  Google Scholar 

  477. Wray V, Kinder R, Federau T, Henklein P, Bechinger B, Schubert U (1999) Solution structure and orientation of the transmembrane anchor domain of the HIV-1-encoded virus protein U by high-resolution and solid-state NMR spectroscopy. Biochemistry 38(16):5272–5282

    Article  PubMed  CAS  Google Scholar 

  478. Kukol A, Arkin IT (1999) vpu transmembrane peptide structure obtained by site-specific fourier transform infrared dichroism and global molecular dynamics searching. Biophys J 77(3):1594–1601

    Article  PubMed  CAS  Google Scholar 

  479. Marassi FM, Ma C, Gratkowski H, Straus SK, Strebel K, Oblatt-Montal M, Montal M, Opella SJ (1999) Correlation of the structural and functional domains in the membrane protein Vpu from HIV-1. Proc Natl Acad Sci USA 96(25):14336–14341

    Article  PubMed  CAS  Google Scholar 

  480. Ma C, Marassi FM, Jones DH, Straus SK, Bour S, Strebel K, Schubert U, Oblatt-Montal M, Montal M, Opella SJ (2002) Expression, purification, and activities of full-length and truncated versions of the integral membrane protein Vpu from HIV-1. Protein Sci 11(3):546–557

    Article  PubMed  CAS  Google Scholar 

  481. 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(2):409–424

    Article  PubMed  CAS  Google Scholar 

  482. Kruger J, Fischer WB (2008) Exploring the conformational space of Vpu from HIV-1: a versatile adaptable protein. J Comput Chem 29(14):2416–2424

    Article  PubMed  CAS  Google Scholar 

  483. Cordes FS, Tustian AD, Sansom MS, Watts A, Fischer WB (2002) Bundles consisting of extended transmembrane segments of Vpu from HIV-1: computer simulations and conductance measurements. Biochemistry 41(23):7359–7365

    Article  PubMed  CAS  Google Scholar 

  484. Mehnert T, Lam YH, Judge PJ, Routh A, Fischer D, Watts A, Fischer WB (2007) Towards a mechanism of function of the viral ion channel Vpu from HIV-1. J Biomol Struct Dyn 24(6):589–596

    PubMed  CAS  Google Scholar 

  485. Becker CF, Oblatt-Montal M, Kochendoerfer GG, Montal M (2004) Chemical synthesis and single channel properties of tetrameric and pentameric TASPs (template-assembled synthetic proteins) derived from the transmembrane domain of HIV virus protein u (Vpu). J Biol Chem 279(17):17483–17489

    Article  PubMed  CAS  Google Scholar 

  486. Mehnert T, Routh A, Judge PJ, Lam YH, Fischer D, Watts A, Fischer WB (2008) Biophysical characterization of Vpu from HIV-1 suggests a channel-pore dualism. Proteins 70(4):1488–1497

    Article  PubMed  CAS  Google Scholar 

  487. Lu JX, Sharpe S, Ghirlando R, Yau WM, Tycko R (2010) Oligomerization state and supramolecular structure of the HIV-1 Vpu protein transmembrane segment in phospholipid bilayers. Protein Sci 19(10):1877–1896

    Article  PubMed  CAS  Google Scholar 

  488. Wray V, Federau T, Henklein P, Klabunde S, Kunert O, Schomburg D, Schubert U (1995) Solution structure of the hydrophilic region of HIV-1 encoded virus protein U (Vpu) by CD and 1H NMR spectroscopy. Int J Pept Protein Res 45(1):35–43

    Article  PubMed  CAS  Google Scholar 

  489. Federau T, Schubert U, Flossdorf J, Henklein P, Schomburg D, Wray V (1996) Solution structure of the cytoplasmic domain of the human immunodeficiency virus type 1 encoded virus protein U (Vpu). Int J Pept Protein Res 47(4):297–310

    Article  PubMed  CAS  Google Scholar 

  490. 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(3):581–588

    Article  PubMed  CAS  Google Scholar 

  491. Coadou G, Evrard-Todeschi N, Gharbi-Benarous J, Benarous R, Girault JP (2002) HIV-1 encoded virus protein U (Vpu) solution structure of the 41–62 hydrophilic region containing the phosphorylated sites Ser52 and Ser56. Int J Biol Macromol 30(1):23–40

    Article  PubMed  CAS  Google Scholar 

  492. Coadou G, Gharbi-Benarous J, Megy S, Bertho G, Evrard-Todeschi N, Segeral E, Benarous R, Girault JP (2003) NMR studies of the phosphorylation motif of the HIV-1 protein Vpu bound to the F-box protein beta-TrCP. Biochemistry 42(50):14741–14751

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Programs of the Russian Academy of Sciences for “Molecular and Cellular Biology” (to V.N.U) and the Killam Memorial Scholarship (to M.J.M.).

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, University of South Florida, College of Medicine, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL, 33612, USA

    Bin Xue & Vladimir N. Uversky

  2. Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB, T6G 2V4, Canada

    Marcin J. Mizianty & Lukasz Kurgan

  3. Institute for Biological Instrumentation, Russian Academy of Sciences, 142290, Pushchino, Moscow Region, Russia

    Vladimir N. Uversky

Authors
  1. Bin Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcin J. Mizianty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lukasz Kurgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladimir N. Uversky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vladimir N. Uversky.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 70 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, B., Mizianty, M.J., Kurgan, L. et al. Protein intrinsic disorder as a flexible armor and a weapon of HIV-1. Cell. Mol. Life Sci. 69, 1211–1259 (2012). https://doi.org/10.1007/s00018-011-0859-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0859-3

Keywords

Search

Navigation