1887

Abstract

Enzootic nasal tumor virus (ENTV) and Jaagsiekte sheep retrovirus (JSRV) are highly related ovine betaretroviruses that induce nasal and lung tumours in small ruminants, respectively. While the ENTV and JSRV envelope (Env) glycoproteins mediate virus entry using the same cellular receptor, the glycosylphosphatidylinositol-linked protein hyaluronoglucosaminidase, ENTV Env pseudovirions mediate entry into cells from a much more restricted range of species than do JSRV Env pseudovirions. Unlike JSRV Env, ENTV Env does not induce cell fusion at pH 5.0 or above, but rather requires a much lower pH (4.0–4.5) for fusion to occur. The cytoplasmic tail of retroviral envelope proteins is a key modulator of envelope-mediated fusion and pseudotype efficiency, especially in the context of virions composed of heterologous Gag proteins. Here we report that progressive truncation of the ENTV Env cytoplasmic tail improves transduction efficiency of pseudotyped retroviral vectors and that complete truncation of the ENTV Env cytoplasmic tail increases transduction efficiency to wild-type JSRV Env levels by increasing fusogenicity without affecting sensitivity to inhibition by lysosomotropic agents, subcellular localization or efficiency of inclusion into virions. Truncation of the cytoplasmic domain of ENTV Env resulted in a significant advantage in viral entry into all cell types tested, including foetal ovine lung and nasal cells. Taken together, we demonstrate that the cytoplasmic tail modulates the fusion activity of the ENTV Env protein and that truncation of this region enhances Eenv-mediated entry into target cells.

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2017-02-06
2019-09-18
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References

  1. Walsh SR, Linnerth-Petrik NM, Yu DL, Foster RA, Menzies PI et al. Experimental transmission of enzootic nasal adenocarcinoma in sheep. Vet Res 2013;44:66 [CrossRef][PubMed]
    [Google Scholar]
  2. Palmarini M, Sharp JM, de Las Heras M, Fan H. Jaagsiekte sheep retrovirus is necessary and sufficient to induce a contagious lung cancer in sheep. J Virol 1999;73:6964–6972[PubMed]
    [Google Scholar]
  3. Walsh SR, Linnerth-Petrik NM, Laporte AN, Menzies PI, Foster RA et al. Full-length genome sequence analysis of enzootic nasal tumor virus reveals an unusually high degree of genetic stability. Virus Res 2010;151:74–87 [CrossRef][PubMed]
    [Google Scholar]
  4. Palmarini M, Datta S, Omid R, Murgia C, Fan H. The long terminal repeat of Jaagsiekte sheep retrovirus is preferentially active in differentiated epithelial cells of the lungs. J Virol 2000;74:5776–5787 [CrossRef][PubMed]
    [Google Scholar]
  5. Yu DL, Linnerth-Petrik NM, Halbert CL, Walsh SR, Miller AD et al. Jaagsiekte sheep retrovirus and enzootic nasal tumor virus promoters drive gene expression in all airway epithelial cells of mice but only induce tumors in the alveolar region of the lungs. J Virol 2011;85:7535–7545 [CrossRef][PubMed]
    [Google Scholar]
  6. Caporale M, Cousens C, Centorame P, Pinoni C, de Las Heras M et al. Expression of the Jaagsiekte sheep retrovirus envelope glycoprotein is sufficient to induce lung tumors in sheep. J Virol 2006;80:8030–8037 [CrossRef][PubMed]
    [Google Scholar]
  7. Wootton SK, Halbert CL, Miller AD. Sheep retrovirus structural protein induces lung tumours. Nature 2005;434:904–907 [CrossRef][PubMed]
    [Google Scholar]
  8. Wootton SK, Halbert CL, Miller AD. Envelope proteins of jaagsiekte sheep retrovirus and enzootic nasal tumor virus induce similar bronchioalveolar tumors in lungs of mice. J Virol 2006;80:9322–9325 [CrossRef][PubMed]
    [Google Scholar]
  9. Miller AD. Hyaluronidase 2 and its intriguing role as a cell-entry receptor for oncogenic sheep retroviruses. Semin Cancer Biol 2008;18:296–301 [CrossRef][PubMed]
    [Google Scholar]
  10. Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI et al. Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc Natl Acad Sci USA 2001;98:4443–4448 [CrossRef][PubMed]
    [Google Scholar]
  11. van Hoeven NS, Miller AD. Improved enzootic nasal tumor virus pseudotype packaging cell lines reveal virus entry requirements in addition to the primary receptor Hyal2. J Virol 2005;79:87–94 [CrossRef][PubMed]
    [Google Scholar]
  12. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 2001;20:499–508 [CrossRef][PubMed]
    [Google Scholar]
  13. Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–2404[PubMed]
    [Google Scholar]
  14. Alberti A, Murgia C, Liu SL, Mura M, Cousens C et al. Envelope-induced cell transformation by ovine betaretroviruses. J Virol 2002;76:5387–5394 [CrossRef][PubMed]
    [Google Scholar]
  15. Dirks C, Duh FM, Rai SK, Lerman MI, Miller AD. Mechanism of cell entry and transformation by enzootic nasal tumor virus. J Virol 2002;76:2141–2149 [CrossRef][PubMed]
    [Google Scholar]
  16. Denesvre C, Carrington C, Corbin A, Takeuchi Y, Cosset FL et al. TM domain swapping of murine leukemia virus and human T-cell leukemia virus envelopes confers different infectious abilities despite similar incorporation into virions. J Virol 1996;70:4380–4386[PubMed]
    [Google Scholar]
  17. Gabuzda DH, Lever A, Terwilliger E, Sodroski J. Effects of deletions in the cytoplasmic domain on biological functions of human immunodeficiency virus type 1 envelope glycoproteins. J Virol 1992;66:3306–3315[PubMed]
    [Google Scholar]
  18. Ritter GD, Mulligan MJ, Lydy SL, Compans RW. Cell fusion activity of the simian immunodeficiency virus envelope protein is modulated by the intracytoplasmic domain. Virology 1993;197:255–264 [CrossRef][PubMed]
    [Google Scholar]
  19. Spies CP, Compans RW. Effects of cytoplasmic domain length on cell surface expression and syncytium-forming capacity of the simian immunodeficiency virus envelope glycoprotein. Virology 1994;203:8–19 [CrossRef][PubMed]
    [Google Scholar]
  20. Marks MS, Woodruff L, Ohno H, Bonifacino JS. Protein targeting by tyrosine- and di-leucine-based signals: evidence for distinct saturable components. J Cell Biol 1996;135:341–354 [CrossRef][PubMed]
    [Google Scholar]
  21. Bhakta SJ, Shang L, Prince JL, Claiborne DT, Hunter E. Mutagenesis of tyrosine and di-leucine motifs in the HIV-1 envelope cytoplasmic domain results in a loss of Env-mediated fusion and infectivity. Retrovirology 2011;8:37 [CrossRef][PubMed]
    [Google Scholar]
  22. Blot V, Lopez-Vergès S, Breton M, Pique C, Berlioz-Torrent C et al. The conserved dileucine- and tyrosine-based motifs in MLV and MPMV envelope glycoproteins are both important to regulate a common Env intracellular trafficking. Retrovirology 2006;3:62 [CrossRef][PubMed]
    [Google Scholar]
  23. Lodge R, Delamarre L, Lalonde JP, Alvarado J, Sanders DA et al. Two distinct oncornaviruses harbor an intracytoplasmic tyrosine-based basolateral targeting signal in their viral envelope glycoprotein. J Virol 1997;71:5696–5702[PubMed]
    [Google Scholar]
  24. Bonifacino JS, Traub LM. Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 2003;72:395–447 [CrossRef][PubMed]
    [Google Scholar]
  25. Bertrand P, Côté M, Zheng YM, Albritton LM, Liu SL. Jaagsiekte sheep retrovirus utilizes a pH-dependent endocytosis pathway for entry. J Virol 2008;82:2555–2559 [CrossRef][PubMed]
    [Google Scholar]
  26. Côté M, Kucharski TJ, Liu SL. Enzootic nasal tumor virus envelope requires a very acidic pH for fusion activation and infection. J Virol 2008;82:9023–9034 [CrossRef][PubMed]
    [Google Scholar]
  27. Bowman EJ, Siebers A, Altendorf K. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc Natl Acad Sci USA 1988;85:7972–7976 [CrossRef][PubMed]
    [Google Scholar]
  28. Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 1986;55:663–700 [CrossRef][PubMed]
    [Google Scholar]
  29. Zhang L, Ghosh HP. Characterization of the putative fusogenic domain in vesicular stomatitis virus glycoprotein G. J Virol 1994;68:2186–2193[PubMed]
    [Google Scholar]
  30. Mcclure MO, Sommerfelt MA, Marsh M, Weiss RA. The pH independence of mammalian retrovirus infection. J Gen Virol 1990;71:767–773 [CrossRef][PubMed]
    [Google Scholar]
  31. Nussbaum O, Roop A, Anderson WF. Sequences determining the pH dependence of viral entry are distinct from the host range-determining region of the murine ecotropic and amphotropic retrovirus envelope proteins. J Virol 1993;67:7402–7405[PubMed]
    [Google Scholar]
  32. Ahn KS, Ou W, Silver J. Inhibition of certain strains of HIV-1 by cell surface polyanions in the form of cholesterol-labeled oligonucleotides. Virology 2004;330:50–61 [CrossRef][PubMed]
    [Google Scholar]
  33. Ou W, Xiong Y, Silver J. Quantification of virus-envelope-mediated cell fusion using a tetracycline transcriptional transactivator: fusion does not correlate with syncytium formation. Virology 2004;324:263–272 [CrossRef][PubMed]
    [Google Scholar]
  34. Hull S, Fan H. Mutational analysis of the cytoplasmic tail of jaagsiekte sheep retrovirus envelope protein. J Virol 2006;80:8069–8080 [CrossRef][PubMed]
    [Google Scholar]
  35. Côté M, Zheng YM, Albritton LM, Liu SL. Fusogenicity of jaagsiekte sheep retrovirus envelope protein is dependent on low pH and is enhanced by cytoplasmic tail truncations. J Virol 2008;82:2543–2554 [CrossRef][PubMed]
    [Google Scholar]
  36. Lam AJ, St-Pierre F, Gong Y, Marshall JD, Cranfill PJ et al. Improving FRET dynamic range with bright green and red fluorescent proteins. Nat Methods 2012;9:1005–1012 [CrossRef][PubMed]
    [Google Scholar]
  37. den Boon JA, Chen J, Ahlquist P. Identification of sequences in brome mosaic virus replicase protein 1a that mediate association with endoplasmic reticulum membranes. J Virol 2001;75:12370–12381 [CrossRef][PubMed]
    [Google Scholar]
  38. Affranchino JL, González SA. Mutations at the C-terminus of the simian immunodeficiency virus envelope glycoprotein affect gp120–gp41 stability on virions. Virology 2006;347:217–225 [CrossRef][PubMed]
    [Google Scholar]
  39. Brody BA, Hunter E. Mutations within the env gene of Mason–Pfizer monkey virus: effects on protein transport and SU–TM association. J Virol 1992;66:3466–3475[PubMed]
    [Google Scholar]
  40. Brody BA, Rhee SS, Hunter E. Postassembly cleavage of a retroviral glycoprotein cytoplasmic domain removes a necessary incorporation signal and activates fusion activity. J Virol 1994;68:4620–4627[PubMed]
    [Google Scholar]
  41. Celma CC, Manrique JM, Affranchino JL, Hunter E, González SA. Domains in the simian immunodeficiency virus gp41 cytoplasmic tail required for envelope incorporation into particles. Virology 2001;283:253–261 [CrossRef][PubMed]
    [Google Scholar]
  42. Song C, Dubay SR, Hunter E. A tyrosine motif in the cytoplasmic domain of mason–pfizer monkey virus is essential for the incorporation of glycoprotein into virions. J Virol 2003;77:5192–5200 [CrossRef][PubMed]
    [Google Scholar]
  43. Bruett L, Clements JE. Functional murine leukemia virus vectors pseudotyped with the visna virus envelope show expanded visna virus cell tropism. J Virol 2001;75:11464–11473 [CrossRef][PubMed]
    [Google Scholar]
  44. Christodoulopoulos I, Cannon PM. Sequences in the cytoplasmic tail of the gibbon ape leukemia virus envelope protein that prevent its incorporation into lentivirus vectors. J Virol 2001;75:4129–4138 [CrossRef][PubMed]
    [Google Scholar]
  45. Höhne M, Thaler S, Dudda JC, Groner B, Schnierle BS. Truncation of the human immunodeficiency virus-type-2 envelope glycoprotein allows efficient pseudotyping of murine leukemia virus retroviral vector particles. Virology 1999;261:70–78 [CrossRef][PubMed]
    [Google Scholar]
  46. Johnston PB, Dubay JW, Hunter E. Truncations of the simian immunodeficiency virus transmembrane protein confer expanded virus host range by removing a block to virus entry into cells. J Virol 1993;67:3077–3086[PubMed]
    [Google Scholar]
  47. Mammano F, Kondo E, Sodroski J, Bukovsky A, Göttlinger HG. Rescue of human immunodeficiency virus type 1 matrix protein mutants by envelope glycoproteins with short cytoplasmic domains. J Virol 1995;69:3824–3830[PubMed]
    [Google Scholar]
  48. Mammano F, Salvatori F, Indraccolo S, de Rossi A, Chieco-Bianchi L et al. Truncation of the human immunodeficiency virus type 1 envelope glycoprotein allows efficient pseudotyping of moloney murine leukemia virus particles and gene transfer into CD4+ cells. J Virol 1997;71:3341–3345[PubMed]
    [Google Scholar]
  49. Funke S, Maisner A, Mühlebach MD, Koehl U, Grez M et al. Targeted cell entry of lentiviral vectors. Mol Ther 2008;16:1427–1436 [CrossRef][PubMed]
    [Google Scholar]
  50. Funke S, Schneider IC, Glaser S, Mühlebach MD, Moritz T et al. Pseudotyping lentiviral vectors with the wild-type measles virus glycoproteins improves titer and selectivity. Gene Ther 2009;16:700–705 [CrossRef][PubMed]
    [Google Scholar]
  51. Giroglou T, Cinatl J, Rabenau H, Drosten C, Schwalbe H et al. Retroviral vectors pseudotyped with severe acute respiratory syndrome coronavirus S protein. J Virol 2004;78:9007–9015 [CrossRef][PubMed]
    [Google Scholar]
  52. Kobayashi M, Iida A, Ueda Y, Hasegawa M. Pseudotyped lentivirus vectors derived from simian immunodeficiency virus SIVagm with envelope glycoproteins from paramyxovirus. J Virol 2003;77:2607–2614 [CrossRef][PubMed]
    [Google Scholar]
  53. Coffin J, Hughes SH, Varmus HE. Retroviruses Plainview, NY: Cold Spring Harbor Laboratory Press; 1997
    [Google Scholar]
  54. Januszeski MM, Cannon PM, Chen D, Rozenberg Y, Anderson WF. Functional analysis of the cytoplasmic tail of moloney murine leukemia virus envelope protein. J Virol 1997;71:3613–3619[PubMed]
    [Google Scholar]
  55. Melikyan GB, Markosyan RM, Brener SA, Rozenberg Y, Cohen FS. Role of the cytoplasmic tail of ecotropic moloney murine leukemia virus Env protein in fusion pore formation. J Virol 2000;74:447–455 [CrossRef][PubMed]
    [Google Scholar]
  56. Ragheb JA, Anderson WF. pH-independent murine leukemia virus ecotropic envelope-mediated cell fusion: implications for the role of the R peptide and p12E TM in viral entry. J Virol 1994;68:3220–3231[PubMed]
    [Google Scholar]
  57. Rein A, Mirro J, Haynes JG, Ernst SM, Nagashima K. Function of the cytoplasmic domain of a retroviral transmembrane protein: p15E-p2E cleavage activates the membrane fusion capability of the murine leukemia virus Env protein. J Virol 1994;68:1773–1781[PubMed]
    [Google Scholar]
  58. Brody BA, Rhee SS, Sommerfelt MA, Hunter E. A viral protease-mediated cleavage of the transmembrane glycoprotein of Mason–Pfizer monkey virus can be suppressed by mutations within the matrix protein. Proc Natl Acad Sci USA 1992;89:3443–3447 [CrossRef][PubMed]
    [Google Scholar]
  59. Rice NR, Henderson LE, Sowder RC, Copeland TD, Oroszlan S et al. Synthesis and processing of the transmembrane envelope protein of equine infectious anemia virus. J Virol 1990;64:3770–3778[PubMed]
    [Google Scholar]
  60. Green N, Shinnick TM, Witte O, Ponticelli A, Sutcliffe JG et al. Sequence-specific antibodies show that maturation of Moloney leukemia virus envelope polyprotein involves removal of a COOH-terminal peptide. Proc Natl Acad Sci USA 1981;78:6023–6027 [CrossRef][PubMed]
    [Google Scholar]
  61. Henderson LE, Sowder R, Copeland TD, Smythers G, Oroszlan S. Quantitative separation of murine leukemia virus proteins by reversed-phase high-pressure liquid chromatography reveals newly described gag and env cleavage products. J Virol 1984;52:492–500[PubMed]
    [Google Scholar]
  62. Zhao Y, Zhu L, Benedict CA, Chen D, Anderson WF et al. Functional domains in the retroviral transmembrane protein. J Virol 1998;72:5392–5398[PubMed]
    [Google Scholar]
  63. Dick RA, Vogt VM. Membrane interaction of retroviral Gag proteins. Front Microbiol 2014;5:187 [CrossRef][PubMed]
    [Google Scholar]
  64. Jorgenson RL, Vogt VM, Johnson MC. Foreign glycoproteins can be actively recruited to virus assembly sites during pseudotyping. J Virol 2009;83:4060–4067 [CrossRef][PubMed]
    [Google Scholar]
  65. Jin S, Zhang B, Weisz OA, Montelaro RC. Receptor-mediated entry by equine infectious anemia virus utilizes a pH-dependent endocytic pathway. J Virol 2005;79:14489–14497 [CrossRef][PubMed]
    [Google Scholar]
  66. Picard-Maureau M, Jarmy G, Berg A, Rethwilm A, Lindemann D. Foamy virus envelope glycoprotein-mediated entry involves a pH-dependent fusion process. J Virol 2003;77:4722–4730 [CrossRef][PubMed]
    [Google Scholar]
  67. Hernandez R, Luo T, Brown DT. Exposure to low pH is not required for penetration of mosquito cells by Sindbis virus. J Virol 2001;75:2010–2013 [CrossRef][PubMed]
    [Google Scholar]
  68. Sinn PL, Penisten AK, Burnight ER, Hickey MA, Williams G et al. Gene transfer to respiratory epithelia with lentivirus pseudotyped with Jaagsiekte sheep retrovirus envelope glycoprotein. Hum Gene Ther 2005;16:479–488 [CrossRef][PubMed]
    [Google Scholar]
  69. Rai SK, Demartini JC, Miller AD. Retrovirus vectors bearing jaagsiekte sheep retrovirus env transduce human cells by using a new receptor localized to chromosome 3p21.3. J Virol 2000;74:4698–4704[PubMed][CrossRef]
    [Google Scholar]
  70. Wang W, Malcolm BA. Two-stage PCR protocol allowing introduction of multiple mutations, deletions and insertions using QuikChange Site-Directed Mutagenesis. Biotechniques 1999;26:680–682[PubMed]
    [Google Scholar]
  71. Miller DG, Edwards RH, Miller AD. Cloning of the cellular receptor for amphotropic murine retroviruses reveals homology to that for gibbon ape leukemia virus. Proc Natl Acad Sci USA 1994;91:78–82 [CrossRef][PubMed]
    [Google Scholar]
  72. Vigdorovich V, Strong RK, Miller AD. Expression and characterization of a soluble, active form of the jaagsiekte sheep retrovirus receptor, Hyal2. J Virol 2005;79:79–86 [CrossRef][PubMed]
    [Google Scholar]
  73. Kimpton J, Emerman M. Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated beta-galactosidase gene. J Virol 1992;66:2232–2239[PubMed]
    [Google Scholar]
  74. Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 2003;9:493–501 [CrossRef][PubMed]
    [Google Scholar]
  75. Schwartz S, Campbell M, Nasioulas G, Harrison J, Felber BK et al. Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression. J Virol 1992;66:7176–7182[PubMed]
    [Google Scholar]
  76. Sherer NM, Lehmann MJ, Jimenez-Soto LF, Ingmundson A, Horner SM et al. Visualization of retroviral replication in living cells reveals budding into multivesicular bodies. Traffic 2003;4:785–801 [CrossRef][PubMed]
    [Google Scholar]
  77. Linnerth-Petrik NM, Santry LA, Yu DL, Wootton SK. Adeno-associated virus vector mediated expression of an oncogenic retroviral envelope protein induces lung adenocarcinomas in immunocompetent mice. PLoS One 2012;7:e51400 [CrossRef][PubMed]
    [Google Scholar]
  78. Wootton SK, Metzger MJ, Hudkins KL, Alpers CE, York D et al. Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV. Retrovirology 2006;3:94 [CrossRef][PubMed]
    [Google Scholar]
  79. Simm M, Shahabuddin M, Chao W, Allan JS, Volsky DJ. Aberrant Gag protein composition of a human immunodeficiency virus type 1 vif mutant produced in primary lymphocytes. J Virol 1995;69:4582–4586[PubMed]
    [Google Scholar]
  80. Nitta T, Tam R, Kim JW, Fan H. The cellular protein La functions in enhancement of virus release through lipid rafts facilitated by murine leukemia virus glycosylated Gag. MBio 2011;2:e00341-10 [CrossRef][PubMed]
    [Google Scholar]
  81. Liu SL, Miller AD. Transformation of madin–darby canine kidney epithelial cells by sheep retrovirus envelope proteins. J Virol 2005;79:927–933 [CrossRef][PubMed]
    [Google Scholar]
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