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Abstract

Influenza A viruses bear an eight-segmented single-stranded negative-sense RNA genome that is replicated in the nucleus. Newly synthesized viral RNA (vRNA) segments are exported from the nucleus and transported to the plasma membrane for packaging into progeny virions. Influenza viruses exploit many host proteins during these events, and this is the portion of the viral life cycle when genetic reassortment among influenza viruses occurs. Reassortment among influenza A viruses allows viruses to expand their host range, virulence, and pandemic potential. This review covers recent studies on the export of vRNAs from the nucleus and their transport through the cytoplasm, progressive assembly, and packaging into progeny virus particles. Understanding these events and the constraints on genetic reassortment has implications for assessment of the pandemic potential of newly emerged influenza viruses, for vaccine production, for determination of viral fitness, and for identification of novel therapeutic targets.

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2016-09-29
2024-04-23
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Literature Cited

  1. Fodor E. 1.  2013. The RNA polymerase of influenza A virus: mechanisms of viral transcription and replication. Acta Virol 57:113–22 [Google Scholar]
  2. Ortin J, Martin-Benito J. 2.  2015. The RNA synthesis machinery of negative-stranded RNA viruses. Virology 479–80:532–44 [Google Scholar]
  3. Arranz R, Coloma R, Chichon FJ, Conesa JJ, Carrascosa JL. 3.  et al. 2012. The structure of native influenza virion ribonucleoproteins. Science 338:1634–37 [Google Scholar]
  4. Moeller A, Kirchdoerfer RN, Potter CS, Carragher B, Wilson IA. 4.  2012. Organization of the influenza virus replication machinery. Science 338:1631–34 [Google Scholar]
  5. Paterson D, Fodor E. 5.  2012. Emerging roles for the influenza A virus nuclear export protein (NEP). PLOS Pathog 8:e1003019 [Google Scholar]
  6. Chou YY, Heaton NS, Gao Q, Palese P, Singer RH, Lionnet T. 6.  2013. Colocalization of different influenza viral RNA segments in the cytoplasm before viral budding as shown by single-molecule sensitivity FISH analysis. PLOS Pathog 9:e1003358 [Google Scholar]
  7. Elton D, Simpson-Holley M, Archer K, Medcalf L, Hallam R. 7.  et al. 2001. Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway. J. Virol. 75:408–19 [Google Scholar]
  8. Momose F, Kikuchi Y, Komase K, Morikawa Y. 8.  2007. Visualization of microtubule-mediated transport of influenza viral progeny ribonucleoprotein. Microbes Infect. 9:1422–33 [Google Scholar]
  9. Watanabe K, Takizawa N, Katoh M, Hoshida K, Kobayashi N, Nagata K. 9.  2001. Inhibition of nuclear export of ribonucleoprotein complexes of influenza virus by leptomycin B. Virus Res 77:31–42 [Google Scholar]
  10. Lakdawala SS, Wu Y, Wawrzusin P, Kabat J, Broadbent AJ. 10.  et al. 2014. Influenza A virus assembly intermediates fuse in the cytoplasm. PLOS Pathog 10:e1003971 [Google Scholar]
  11. Chase GP, Rameix-Welti MA, Zvirbliene A, Zvirblis G, Gotz V. 11.  et al. 2011. Influenza virus ribonucleoprotein complexes gain preferential access to cellular export machinery through chromatin targeting. PLOS Pathog 7:e1002187 [Google Scholar]
  12. Brunotte L, Flies J, Bolte H, Reuther P, Vreede F, Schwemmle M. 12.  2014. The nuclear export protein of H5N1 influenza A viruses recruits Matrix 1 (M1) protein to the viral ribonucleoprotein to mediate nuclear export. J. Biol. Chem. 289:20067–77 [Google Scholar]
  13. Hengrung N, El Omari K, Serna Martin I, Vreede FT, Cusack S. 13.  et al. 2015. Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. Nature 527:114–17 [Google Scholar]
  14. Pflug A, Guilligay D, Reich S, Cusack S. 14.  2014. Structure of influenza A polymerase bound to the viral RNA promoter. Nature 516:355–60 [Google Scholar]
  15. Reich S, Guilligay D, Pflug A, Malet H, Berger I. 15.  et al. 2014. Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Nature 516:361–66 [Google Scholar]
  16. Thierry E, Guilligay D, Kosinski J, Bock T, Gaudon S. 16.  et al. 2016. Influenza polymerase can adopt an alternative configuration involving a radical repacking of PB2 domains. Mol. Cell 61:125–37 [Google Scholar]
  17. York A, Hengrung N, Vreede FT, Huiskonen JT, Fodor E. 17.  2013. Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus. PNAS 110:E4238–45 [Google Scholar]
  18. Tchatalbachev S, Flick R, Hobom G. 18.  2001. The packaging signal of influenza viral RNA molecules. RNA 7:979–89 [Google Scholar]
  19. O'Neill RE, Talon J, Palese P. 19.  1998. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 17:288–96 [Google Scholar]
  20. Neumann G, Hughes MT, Kawaoka Y. 20.  2000. Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1. EMBO J 19:6751–58 [Google Scholar]
  21. Yu M, Liu X, Cao S, Zhao Z, Zhang K. 21.  et al. 2012. Identification and characterization of three novel nuclear export signals in the influenza A virus nucleoprotein. J. Virol. 86:4970–80 [Google Scholar]
  22. Bui M, Wills EG, Helenius A, Whittaker GR. 22.  2000. Role of the influenza virus M1 protein in nuclear export of viral ribonucleoproteins. J. Virol. 74:1781–86 [Google Scholar]
  23. Cao S, Liu X, Yu M, Li J, Jia X. 23.  et al. 2012. A nuclear export signal in the matrix protein of influenza A virus is required for efficient virus replication. J. Virol. 86:4883–91 [Google Scholar]
  24. Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T. 24.  et al. 2003. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 22:2717–28 [Google Scholar]
  25. Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O. 25.  et al. 2001. Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat. Cell Biol. 3:301–5 [Google Scholar]
  26. Chua MA, Schmid S, Perez JT, Langlois RA, Tenoever BR. 26.  2013. Influenza A virus utilizes suboptimal splicing to coordinate the timing of infection. Cell Rep 3:23–29 [Google Scholar]
  27. Amorim MJ, Bruce EA, Read EK, Foeglein A, Mahen R. 27.  et al. 2011. A Rab11- and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA. J. Virol. 85:4143–56 [Google Scholar]
  28. Arcangeletti MC, De Conto F, Ferraglia F, Pinardi F, Gatti R. 28.  et al. 2008. Host-cell-dependent role of actin cytoskeleton during the replication of a human strain of influenza A virus. Arch. Virol. 153:1209–21 [Google Scholar]
  29. Kumakura M, Kawaguchi A, Nagata K. 29.  2015. Actin-myosin network is required for proper assembly of influenza virus particles. Virology 476:141–50 [Google Scholar]
  30. Roberts PC, Compans RW. 30.  1998. Host cell dependence of viral morphology. PNAS 95:5746–51 [Google Scholar]
  31. Simpson-Holley M, Ellis D, Fisher D, Elton D, McCauley J, Digard P. 31.  2002. A functional link between the actin cytoskeleton and lipid rafts during budding of filamentous influenza virions. Virology 301:212–25 [Google Scholar]
  32. Avilov SV, Moisy D, Munier S, Schraidt O, Naffakh N, Cusack S. 32.  2012. Replication-competent influenza A virus that encodes a split-green fluorescent protein-tagged PB2 polymerase subunit allows live-cell imaging of the virus life cycle. J. Virol. 86:1433–48 [Google Scholar]
  33. Bruce EA, Digard P, Stuart AD. 33.  2010. The Rab11 pathway is required for influenza A virus budding and filament formation. J. Virol. 84:5848–59 [Google Scholar]
  34. Eisfeld AJ, Kawakami E, Watanabe T, Neumann G, Kawaoka Y. 34.  2011. RAB11A is essential for transport of the influenza virus genome to the plasma membrane. J. Virol. 85:6117–26 [Google Scholar]
  35. Weisz OA, Rodriguez-Boulan E. 35.  2009. Apical trafficking in epithelial cells: signals, clusters and motors. J. Cell Sci. 122:4253–66 [Google Scholar]
  36. Welz T, Wellbourne-Wood J, Kerkhoff E. 36.  2014. Orchestration of cell surface proteins by Rab11. Trends Cell Biol 24:407–15 [Google Scholar]
  37. Bruce EA, Stuart A, McCaffrey MW, Digard P. 37.  2012. Role of the Rab11 pathway in negative-strand virus assembly. Biochem. Soc. Trans. 40:1409–15 [Google Scholar]
  38. Guichard A, Nizet V, Bier E. 38.  2014. RAB11-mediated trafficking in host-pathogen interactions. Nat. Rev. Microbiol. 12:624–34 [Google Scholar]
  39. Avilov SV, Moisy D, Naffakh N, Cusack S. 39.  2012. Influenza A virus progeny vRNP trafficking in live infected cells studied with the virus-encoded fluorescently tagged PB2 protein. Vaccine 30:7411–17 [Google Scholar]
  40. Hutchinson EC, Charles PD, Hester SS, Thomas B, Trudgian D. 40.  et al. 2014. Conserved and host-specific features of influenza virion architecture. Nat. Commun. 5:4816 [Google Scholar]
  41. Shaw ML, Stone KL, Colangelo CM, Gulcicek EE, Palese P. 41.  2008. Cellular proteins in influenza virus particles. PLOS Pathog 4:e1000085 [Google Scholar]
  42. Chen BJ, Leser GP, Jackson D, Lamb RA. 42.  2008. The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding. J. Virol. 82:10059–70 [Google Scholar]
  43. Iwatsuki-Horimoto K, Horimoto T, Noda T, Kiso M, Maeda J. 43.  et al. 2006. The cytoplasmic tail of the influenza A virus M2 protein plays a role in viral assembly. J. Virol. 80:5233–40 [Google Scholar]
  44. McCown MF, Pekosz A. 44.  2005. The influenza A virus M2 cytoplasmic tail is required for infectious virus production and efficient genome packaging. J. Virol. 79:3595–605 [Google Scholar]
  45. Zhang J, Leser GP, Pekosz A, Lamb RA. 45.  2000. The cytoplasmic tails of the influenza virus spike glycoproteins are required for normal genome packaging. Virology 269:325–34 [Google Scholar]
  46. Grantham ML, Stewart SM, Lalime EN, Pekosz A. 46.  2010. Tyrosines in the influenza A virus M2 protein cytoplasmic tail are critical for production of infectious virus particles. J. Virol. 84:8765–76 [Google Scholar]
  47. Momose F, Sekimoto T, Ohkura T, Jo S, Kawaguchi A. 47.  et al. 2011. Apical transport of influenza A virus ribonucleoprotein requires Rab11-positive recycling endosome. PLOS ONE 6:e21123 [Google Scholar]
  48. Watanabe S, Mabuchi K, Ikebe R, Ikebe M. 48.  2006. Mechanoenzymatic characterization of human myosin Vb. Biochemistry 45:2729–38 [Google Scholar]
  49. Hutchinson EC, von Kirchbach JC, Gog JR, Digard P. 49.  2010. Genome packaging in influenza A virus. J. Gen. Virol. 91:313–28 [Google Scholar]
  50. Gerber M, Isel C, Moules V, Marquet R. 50.  2014. Selective packaging of the influenza A genome and consequences for genetic reassortment. Trends Microbiol 22:446–55 [Google Scholar]
  51. Brooke CB, Ince WL, Wrammert J, Ahmed R, Wilson PC. 51.  et al. 2013. Most influenza A virions fail to express at least one essential viral protein. J. Virol. 87:3155–62 [Google Scholar]
  52. Duhaut SD, McCauley JW. 52.  1996. Defective RNAs inhibit the assembly of influenza virus genome segments in a segment-specific manner. Virology 216:326–37 [Google Scholar]
  53. Odagiri T, Tashiro M. 53.  1997. Segment-specific noncoding sequences of the influenza virus genome RNA are involved in the specific competition between defective interfering RNA and its progenitor RNA segment at the virion assembly step. J. Virol. 71:2138–45 [Google Scholar]
  54. Noda T, Sagara H, Yen A, Takada A, Kida H. 54.  et al. 2006. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature 439:490–92 [Google Scholar]
  55. Fournier E, Moules V, Essere B, Paillart JC, Sirbat JD. 55.  et al. 2012. A supramolecular assembly formed by influenza A virus genomic RNA segments. Nucleic Acids Res 40:2197–209 [Google Scholar]
  56. Noda T, Sugita Y, Aoyama K, Hirase A, Kawakami E. 56.  et al. 2012. Three-dimensional analysis of ribonucleoprotein complexes in influenza A virus. Nat. Commun. 3:639 [Google Scholar]
  57. Sugita Y, Sagara H, Noda T, Kawaoka Y. 57.  2013. Configuration of viral ribonucleoprotein complexes within the influenza A virion. J. Virol. 87:12879–84 [Google Scholar]
  58. Chou YY, Vafabakhsh R, Doganay S, Gao Q, Ha T, Palese P. 58.  2012. One influenza virus particle packages eight unique viral RNAs as shown by FISH analysis. PNAS 109:9101–6 [Google Scholar]
  59. Fujii K, Fujii Y, Noda T, Muramoto Y, Watanabe T. 59.  et al. 2005. Importance of both the coding and the segment-specific noncoding regions of the influenza A virus NS segment for its efficient incorporation into virions. J. Virol. 79:3766–74 [Google Scholar]
  60. Fujii Y, Goto H, Watanabe T, Yoshida T, Kawaoka Y. 60.  2003. Selective incorporation of influenza virus RNA segments into virions. PNAS 100:2002–7 [Google Scholar]
  61. Hutchinson EC, Curran MD, Read EK, Gog JR, Digard P. 61.  2008. Mutational analysis of cis-acting RNA signals in segment 7 of influenza A virus. J. Virol. 82:11869–79 [Google Scholar]
  62. Liang Y, Hong Y, Parslow TG. 62.  2005. cis-Acting packaging signals in the influenza virus PB1, PB2, and PA genomic RNA segments. J. Virol. 79:10348–55 [Google Scholar]
  63. Marsh GA, Hatami R, Palese P. 63.  2007. Specific residues of the influenza A virus hemagglutinin viral RNA are important for efficient packaging into budding virions. J. Virol. 81:9727–36 [Google Scholar]
  64. Marsh GA, Rabadan R, Levine AJ, Palese P. 64.  2008. Highly conserved regions of influenza A virus polymerase gene segments are critical for efficient viral RNA packaging. J. Virol. 82:2295–304 [Google Scholar]
  65. Gog JR, Afonso Edos S, Dalton RM, Leclercq I, Tiley L. 65.  et al. 2007. Codon conservation in the influenza A virus genome defines RNA packaging signals. Nucleic Acids Res 35:1897–907 [Google Scholar]
  66. Goto H, Muramoto Y, Noda T, Kawaoka Y. 66.  2013. The genome-packaging signal of the influenza A virus genome comprises a genome incorporation signal and a genome-bundling signal. J. Virol. 87:11316–22 [Google Scholar]
  67. Hutchinson EC, Wise HM, Kudryavtseva K, Curran MD, Digard P. 67.  2009. Characterisation of influenza A viruses with mutations in segment 5 packaging signals. Vaccine 27:6270–75 [Google Scholar]
  68. Muramoto Y, Takada A, Fujii K, Noda T, Iwatsuki-Horimoto K. 68.  et al. 2006. Hierarchy among viral RNA (vRNA) segments in their role in vRNA incorporation into influenza A virions. J. Virol. 80:2318–25 [Google Scholar]
  69. Ozawa M, Maeda J, Iwatsuki-Horimoto K, Watanabe S, Goto H. 69.  et al. 2009. Nucleotide sequence requirements at the 5′ end of the influenza A virus M RNA segment for efficient virus replication. J. Virol. 83:3384–88 [Google Scholar]
  70. Fournier E, Moules V, Essere B, Paillart JC, Sirbat JD. 70.  et al. 2012. Interaction network linking the human H3N2 influenza A virus genomic RNA segments. Vaccine 30:7359–67 [Google Scholar]
  71. Gavazzi C, Isel C, Fournier E, Moules V, Cavalier A. 71.  et al. 2013. An in vitro network of intermolecular interactions between viral RNA segments of an avian H5N2 influenza A virus: comparison with a human H3N2 virus. Nucleic Acids Res 41:1241–54 [Google Scholar]
  72. Gavazzi C, Yver M, Isel C, Smyth RP, Rosa-Calatrava M. 72.  et al. 2013. A functional sequence-specific interaction between influenza A virus genomic RNA segments. PNAS 110:16604–9 [Google Scholar]
  73. Zhao L, Peng Y, Zhou K, Cao M, Wang J. 73.  et al. 2014. New insights into the nonconserved noncoding region of the subtype-determinant hemagglutinin and neuraminidase segments of influenza A viruses. J. Virol. 88:11493–503 [Google Scholar]
  74. Cobbin JC, Ong C, Verity E, Gilbertson BP, Rockman SP, Brown LE. 74.  2014. Influenza virus PB1 and neuraminidase gene segments can cosegregate during vaccine reassortment driven by interactions in the PB1 coding region. J. Virol. 88:8971–80 [Google Scholar]
  75. Brooke CB, Ince WL, Wei JJ, Bennink JR, Yewdell JW. 75.  2014. Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility. PNAS 111:16854–59 [Google Scholar]
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Supplemental Material

    Inverted selective plane illumination microscopy video of Madin-Darby canine kidney (MDCK) cells infected with influenza A/WSN/33 PA-green fluorescent protein (GFP). MDCK cells were infected for 16 h and imaged for 30 min with an entire cell volume captured every 2 s. Scale bar = 10 μm. Video reproduced with permission from Reference 10.

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