Dokument

Zusammenfassung:
In der Influenza-Impfstoffproduktion ist es von essentieller Bedeutung, gewünschte Antigene (Hämagglutinin und Neuraminidase) in möglichst kurzer Zeit zu erhalten, damit die Bevölkerung gegen die kommenden Influenzaviren schnell und bestmöglich geschützt ist. Derzeit werden die Saatviren in Eiern hergestellt. Dem Wechsel vom humanen Wirt auf Eier folgen bei vielen Viren Mutationen in den beiden Oberflächen-proteinen HA und NA. Diese Veränderungen konnten während der Passagierung von humanen Influenzaisolaten in Eiern gesehen werden. Je weniger Veränderungen die Viren zu humanen Isolaten aufweisen, desto besser kann der spätere Impfstoff schützen, daher ist die Verwendung von Säugerzellen für die Impfstoffproduktion von Vorteil. Weiterhin ist es wichtig, Impfstoff in ausreichenden Mengen zu Beginn einer jeden neuen Grippesaison verfügbar zu haben. Um ein schnelles und ertragreiches Virus-wachstum zu erzielen, ist die Verwendung eines Donorvirus, dessen positive Wachs-tumseigenschaften auf ein Impfvirus übertragen werden, von besonderer Bedeutung. Dazu ist das Wachstum des Donorstammes im verwendeten Wirtssystem entscheidend. Durch mehrfache Passagierung eines Virus aus einer Patientenprobe wurde ein für die MDCK Zelle passendes Donorvirus (NB # 105) etabliert. Die Morphologie des Virus än-derte sich während der Passagierung vom filamentösen Wildtyp-Charakter hin zu sphä-rischen Partikeln. Außerdem zeigten sich Mutationen im HA, welche die Präferenz des Virus zu α2-3 Sialinsäurebindung änderten. Daher wächst NB # 105 deutlich besser und schneller als der bisher verwendete Donorstamm PR8 NYMC sowohl auf der MDCK33016 PF Zelle als auch in Eiern. PR8 RKI zeigte höhere Titer als PR8 NYMC, aber niedrigere Titer als NB # 105. Eine Untersuchung der NA-Aktivität lässt den Rückschluss zu, dass NB # 105 eine optimale Balance zwischen NA-Aktivität und HA-Bindung besitzt, welche beide PR8 Viren nicht erreichen. Durch die hohen Titer, sowohl auf der MDCK33016 PF Zelle als auch in Eiern, könnte man NB # 105 für die Reassortierung in diesen Systemen verwenden. Austausche des HA und NA in einem RG System zeigten, dass sich NB # 105 als Donorvirus zur Herstellung von Reassortanten mit H1N1 und H3N2 Viren eignet, und dass für einige HA/NA Kombinationen (A/California/07/09 und A/Uruguay/716/07) zu höheren Titern wachsende Reassortanten generiert werden konnten als mit dem Laborstamm PR8 NYMC

Bibliographie / References

1. Wang, P., Palese, P. & O'Neill, R. E. (1997).The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal. J Virol 71, 1850-1856.
2. Widjaja, L., Ilyushina, N., Webster, R. G. & Webby, R. J. (2006).Molecular changes associated with adaptation of human influenza A virus in embryonated chicken eggs. Virology 350, 137-145.
3. Scholtissek, C., Ludwig, S. & Fitch, W. M. (1993).Analysis of influenza A virus nucleoproteins for the assessment of molecular genetic mechanisms leading to new phylogenetic virus lineages. Arch Virol 131, 237-250.
4. Ludwig, S., Wolff, T., Ehrhardt, C., Wurzer, W. J., Reinhardt, J., Planz, O. & Pleschka, S. (2004).MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett 561, 37-43.
5. Yuan, P., Bartlam, M., Lou, Z., Chen, S., Zhou, J., He, X., Lv, Z., Ge, R., Li, X., Deng, T., Fodor, E., Rao, Z. & Liu, Y. (2009).Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458, 909-913.
6. Gabriel, G., Dauber, B., Wolff, T., Planz, O., Klenk, H. D. & Stech, J. (2005).The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A 102, 18590-18595.
7. Treanor, J. J., Betts, R. F., Smith, G. E., Anderson, E. L., Hackett, C. S., Wilkinson, B. E., Belshe, R. B. & Powers, D. C. (1996).Evaluation of a recombinant hemagglutinin expressed in insect cells as an influenza vaccine in young and elderly adults. J Infect Dis 173, 1467-1470.
8. Ludwig, S. (2009).Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti- influenza therapy. J Antimicrob Chemother 64, 1-4.
9. Robb, N. C., Smith, M., Vreede, F. T. & Fodor, E. (2009).NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol 90, 1398-1407.
10. Gabriel, G., Abram, M., Keiner, B., Wagner, R., Klenk, H. D. & Stech, J. (2007).Differential polymerase activity in avian and mammalian cells determines host range of influenza virus. J Virol 81, 9601- 9604.
11. Ortega, J., Martin-Benito, J., Zurcher, T., Valpuesta, J. M., Carrascosa, J. L. & Ortin, J. (2000).Ultrastructural and functional analyses of recombinant influenza virus ribonucleoproteins suggest dimerization of nucleoprotein during virus amplification. J Virol 74, 156-163.
12. Scheiffele, P., Rietveld, A., Wilk, T. & Simons, K. (1999).Influenza viruses select ordered lipid domains during budding from the plasma membrane. J Biol Chem 274, 2038-2044.
13. Hale, B. G., Knebel, A., Botting, C. H., Galloway, C. S., Precious, B. L., Jackson, D., Elliott, R. M. & Randall, R. E. (2009).CDK/ERK-mediated phosphorylation of the human influenza A virus NS1 protein at threonine-215. Virology 383, 6-11.
14. Baum, L. G. & Paulson, J. C. (1990).Sialyloligosaccharides of the respiratory epithelium in the selection of human influenza virus receptor specificity. Acta Histochem Suppl 40, 35-38.
15. Wessling, M. (2009).Adjuvantien in Grippeimpfstoffen – MF59. ImpfDialog 2, 44-46.
16. Grassauer, A., Egorov, A. Y., Ferko, B., Romanova, I., Katinger, H. & Muster, T. (1998).A host restriction-based selection system for influenza haemagglutinin transfectant viruses. J Gen Virol 79 ( Pt 6), 1405-1409.
17. Williams, S. P. & Robertson, J. S. (1993).Analysis of the restriction to the growth of nonegg-adapted human influenza virus in eggs. Virology 196, 660-665.
18. Stanley, W. M. (1944).AN EVALUATION OF METHODS FOR THE CONCENTRATION AND PURIFICATION OF INFLUENZA VIRUS. J Exp Med 79, 255-266.
19. Chen, W., Calvo, P. A., Malide, D., Gibbs, J., Schubert, U., Bacik, I., Basta, S., O'Neill, R., Schickli, J., Palese, P., Henklein, P., Bennink, J. R. & Yewdell, J. W. (2001).A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7, 1306-1312.
20. Schnitzler, S. U. & Schnitzler, P. (2009).An update on swine-origin influenza virus A/H1N1: a review. Virus Genes.
21. Gregersen, J. P. (2008a).A quantitative risk assessment of exposure to adventitious agents in a cell culture-derived subunit influenza vaccine. Vaccine 26, 3332-3340.
22. Gregersen, J. P. (2008b).A risk-assessment model to rate the occurrence and relevance of adventitious agents in the production of influenza vaccines. Vaccine 26, 3297-3304.
23. Goto, H. & Kawaoka, Y. (2000).Assays for functional binding of plasminogen to viral proteins. Methods 21, 159-163.
24. Matrosovich, M. N., Gambaryan, A. S., Teneberg, S., Piskarev, V. E., Yamnikova, S. S., Lvov, D. K., Robertson, J. S. & Karlsson, K. A. (1997).Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. Virology 233, 224-234.
25. Safdar, A. & Cox, M. M. (2007).Baculovirus-expressed influenza vaccine. A novel technology for safe and expeditious vaccine production for human use. Expert Opin Investig Drugs 16, 927-934.
26. Subbarao, K., Klimov, A., Katz, J., Regnery, H., Lim, W., Hall, H., Perdue, M., Swayne, D., Bender, C., Huang, J., Hemphill, M., Rowe, T., Shaw, M., Xu, X., Fukuda, K. & Cox, N. (1998).Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279, 393-396.
27. Rohm, C., Zhou, N., Suss, J., Mackenzie, J. & Webster, R. G. (1996).Characterization of a novel influenza hemagglutinin, H15: criteria for determination of influenza A subtypes. Virology 217, 508-516.
28. Voeten, J. T., Brands, R., Palache, A. M., van Scharrenburg, G. J., Rimmelzwaan, G. F., Osterhaus, A. D. & Claas, E. C. (1999).Characterization of high-growth reassortant influenza A viruses generated in MDCK cells cultured in serum-free medium. Vaccine 17, 1942-1950.
29. Zhirnov, O. P. & Klenk, H. D. (2007).Control of apoptosis in influenza virus-infected cells by up- regulation of Akt and p53 signaling. Apoptosis 12, 1419-1432.
30. Romanova, J., Katinger, D., Ferko, B., Voglauer, R., Mochalova, L., Bovin, N., Lim, W., Katinger, H. & Egorov, A. (2003).Distinct host range of influenza H3N2 virus isolates in Vero and MDCK cells is determined by cell specific glycosylation pattern. Virology 307, 90-97.
31. Ponimaskin, E. & Schmidt, M. F. (1998).Domain-structure of cytoplasmic border region is main determinant for palmitoylation of influenza virus hemagglutinin (H7). Virology 249, 325-335.
32. Gambaryan, A. S., Robertson, J. S. & Matrosovich, M. N. (1999).Effects of egg-adaptation on the receptor-binding properties of human influenza A and B viruses. Virology 258, 232-239.
33. Wanitchang, A., Kramyu, J. & Jongkaewwattana, A. (2010).Enhancement of reverse genetics-derived swine-origin H1N1 influenza virus seed vaccine growth by inclusion of indigenous polymerase PB1 protein. Virus Res 147, 145-148.
34. Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. (1992).Evolution and ecology of influenza A viruses. Microbiol Rev 56, 152-179.
35. Gorman, O. T., Donis, R. O., Kawaoka, Y. & Webster, R. G. (1990b).Evolution of influenza A virus PB2 genes: implications for evolution of the ribonucleoprotein complex and origin of human influenza A virus. J Virol 64, 4893-4902.
36. Gorman, O. T., Bean, W. J., Kawaoka, Y. & Webster, R. G. (1990a).Evolution of the nucleoprotein gene of influenza A virus. J Virol 64, 1487-1497.
37. Chen, Z., Wang, W., Zhou, H., Suguitan, A. L., Jr., Shambaugh, C., Kim, L., Zhao, J., Kemble, G. & Jin, H. (2010).Generation of live attenuated novel influenza virus A/California/7/09 (H1N1) vaccines with high yield in embryonated chicken eggs. J Virol 84, 44-51.
38. Schwarzer, J., Rapp, E., Hennig, R., Genzel, Y., Jordan, I., Sandig, V. & Reichl, U. (2009).Glycan analysis in cell culture-based influenza vaccine production: influence of host cell line and virus strain on the glycosylation pattern of viral hemagglutinin. Vaccine 27, 4325-4336.
39. Gagneux, P., Cheriyan, M., Hurtado-Ziola, N., van der Linden, E. C., Anderson, D., McClure, H., Varki, A. & Varki, N. M. (2003).Human-specific regulation of alpha 2-6-linked sialic acids. J Biol Chem 278, 48245-48250.
40. Meyer, W. J., Wood, J. M., Major, D., Robertson, J. S., Webster, R. G. & Katz, J. M. (1993).Influence of host cell-mediated variation on the international surveillance of influenza A (H3N2) viruses. Virology 196, 130-137.
41. Shi, L., Summers, D. F., Peng, Q. & Galarz, J. M. (1995).Influenza A virus RNA polymerase subunit PB2 is the endonuclease which cleaves host cell mRNA and functions only as the trimeric enzyme. Virology 208, 38-47.
42. Pinto, L. H., Holsinger, L. J. & Lamb, R. A. (1992).Influenza virus M2 protein has ion channel activity. Cell 69, 517-528.
43. Anwar, T., Lal, S. K. & Khan, A. U. (2006).In silico analysis of genes nucleoprotein, neuraminidase and hemagglutinin: a comparative study on different strains of influenza A (Bird flu) virus sub-type H5N1. In Silico Biol 6, 161-168.
44. Herrler, G., Nagele, A., Meier-Ewert, H., Bhown, A. S. & Compans, R. W. (1981).Isolation and structural analysis of influenza C virion glycoproteins. Virology 113, 439-451.
45. Marjuki, H., Alam, M. I., Ehrhardt, C., Wagner, R., Planz, O., Klenk, H. D., Ludwig, S. & Pleschka, S. (2006).Membrane accumulation of influenza A virus hemagglutinin triggers nuclear export of the viral genome via protein kinase Calpha-mediated activation of ERK signaling. J Biol Chem 281, 16707-16715.
46. Novartis Pharma Schweiz AG (2007).MF59 – der Wirkverstärker für Grippeimpfstoffe. Health & Science, 12-13.
47. Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. (2001).Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840-1842.
48. Biswas, S. K. & Nayak, D. P. (1994).Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol 68, 1819-1826.
49. Zhirnov, O. P., Konakova, T. E., Wolff, T. & Klenk, H. D. (2002).NS1 protein of influenza A virus down- regulates apoptosis. J Virol 76, 1617-1625.
50. Neumann, G., Castrucci, M. R. & Kawaoka, Y. (1997).Nuclear import and export of influenza virus nucleoprotein. J Virol 71, 9690-9700.
51. Whittaker, G., Bui, M. & Helenius, A. (1996).Nuclear trafficking of influenza virus ribonuleoproteins in heterokaryons. J Virol 70, 2743-2756.
52. Martin, K. & Helenius, A. (1991).Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell 67, 117-130.
53. Modrow, S., Falke, D. & Truyen, U. (2003).Orthomyxoviren. In Molekulare Virologie, 2 edn, pp. 317-342: Spektrum.
54. Zell, R., Krumbholz, A., Eitner, A., Krieg, R., Halbhuber, K. J. & Wutzler, P. (2007).Prevalence of PB1- F2 of influenza A viruses. J Gen Virol 88, 536-546.
55. Rogers, G. N. & Paulson, J. C. (1983).Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127, 361-373.
56. Bourmakina, S. V. & Garcia-Sastre, A. (2003).Reverse genetics studies on the filamentous morphology of influenza A virus. J Gen Virol 84, 517-527.
57. Pleschka, S. (2008).RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade. Biol Chem 389, 1273-1282.
58. Mizumura, K., Hashimoto, S., Maruoka, S., Gon, Y., Kitamura, N., Matsumoto, K., Hayashi, S., Shimizu, K. & Horie, T. (2003).Role of mitogen-activated protein kinases in influenza virus induction of prostaglandin E2 from arachidonic acid in bronchial epithelial cells. Clin Exp Allergy 33, 1244- 1251.
59. Xing, Z., Cardona, C. J., Anunciacion, J., Adams, S. & Dao, N. (2010).Roles of the ERK MAPK in the regulation of proinflammatory and apoptotic responses in chicken macrophages infected with H9N2 avian influenza virus. J Gen Virol 91, 343-351.
60. Treanor, J. J., Schiff, G. M., Hayden, F. G., Brady, R. C., Hay, C. M., Meyer, A. L., Holden-Wiltse, J., Liang, H., Gilbert, A. & Cox, M. (2007).Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: a randomized controlled trial. JAMA 297, 1577-1582.
61. Schmitt, H. J., Gregersen, J. P., Trusheim, H. & Broeker, M. (2010).Sicherheit von Influenza-Impfstoffen auf Zellkulturbasis. Medizinische Monatsschrift für Pharmazeuten 33, 4-10.
62. Rogers, G. N., Paulson, J. C., Daniels, R. S., Skehel, J. J., Wilson, I. A. & Wiley, D. C. (1983).Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity. Nature 304, 76-78.
63. Zhirnov, O. P., Vorobjeva, I. V., Saphonova, O. A., Malyshev, N. A., Ovcharenko, A. V. & Klenk, H. D. (2007).Specific biochemical features of replication of clinical influenza viruses in human intestinal cell culture. Biochemistry (Mosc ) 72, 398-408.
64. Chen, Z., Aspelund, A. & Jin, H. (2008).Stabilizing the glycosylation pattern of influenza B hemagglutinin following adaptation to growth in eggs. Vaccine 26, 361-371.
65. Zhirnov, O. P., Vorobjeva, I. V., Saphonova, O. A., Poyarkov, S. V., Ovcharenko, A. V., Anhlan, D. & Malyshev, N. A. (2009).Structural and evolutionary characteristics of HA, NA, NS and M genes of clinical influenza A/H3N2 viruses passaged in human and canine cells. J Clin Virol 45, 322-333.
66. Sugrue, R. J. & Hay, A. J. (1991).Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel. Virology 180, 617-624.
67. Xu, X., Zhu, X., Dwek, R. A., Stevens, J. & Wilson, I. A. (2008).Structural characterization of the 1918 influenza virus H1N1 neuraminidase. J Virol 82, 10493-10501.
68. Weis, W., Brown, J. H., Cusack, S., Paulson, J. C., Skehel, J. J. & Wiley, D. C. (1988).Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature 333, 426-431.
69. Tashiro, M., Ciborowski, P., Reinacher, M., Pulverer, G., Klenk, H. D. & Rott, R. (1987).Synergistic role of staphylococcal proteases in the induction of influenza virus pathogenicity. Virology 157, 421- 430.
70. Gerdil, C. (2003).The annual production cycle for influenza vaccine. Vaccine 21, 1776-1779.
71. Stohr, K. (2003).The global agenda on influenza surveillance and control. Vaccine 21, 1744-1748.
72. Schroeder, C., Heider, H., Moncke-Buchner, E. & Lin, T. I. (2005).The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein. Eur Biophys J 34, 52-66.
73. Portela, A. & Digard, P. (2002).The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 83, 723-734.
74. Pinto, L. H. & Lamb, R. A. (2006).The M2 proton channels of influenza A and B viruses. J Biol Chem 281, 8997-9000.
75. Trusheim H., Roth B., Wilms R., Jung S., Muth R., Eggers M., Elsen M., Lenz-Bauer C., Schwarz K., Schneider S., Kreibich S., Dittmar L., Veit E., Schaar T. (2007). The MDCK 33016-PF cell line is not only suitable for the production of cell-based Influenza vaccine but is also an ideal substrate for Influenza virus isolation. Options for the Control of Influenza VI, Toronto, Kanada Ulmanen, I., Broni, B. A. & Krug, R. M. (1981).Role of two of the influenza virus core P proteins in recognizing cap 1 structures (m7GpppNm) on RNAs and in initiating viral RNA transcription. Proc Natl Acad Sci U S A 78, 7355-7359.
76. Ye, Q., Krug, R. M. & Tao, Y. J. (2006).The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444, 1078-1082.
77. Salomon, R., Franks, J., Govorkova, E. A., Ilyushina, N. A., Yen, H. L., Hulse-Post, D. J., Humberd, J., Trichet, M., Rehg, J. E., Webby, R. J., Webster, R. G. & Hoffmann, E. (2006).The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med 203, 689-697.
78. Guilligay, D., Tarendeau, F., Resa-Infante, P., Coloma, R., Crepin, T., Sehr, P., Lewis, J., Ruigrok, R. W., Ortin, J., Hart, D. J. & Cusack, S. (2008).The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15, 500-506.
79. Beaton, A. R. & Krug, R. M. (1986).Transcription antitermination during influenza viral template RNA synthesis requires the nucleocapsid protein and the absence of a 5' capped end. Proc Natl Acad Sci U S A 83, 6282-6286.
80. Hay, A. J., Lomniczi, B., Bellamy, A. R. & Skehel, J. J. (1977).Transcription of the influenza virus genome. Virology 83, 337-355.
81. Ulmer, J. B., Valley, U. & Rappuoli, R. (2006).Vaccine manufacturing: challenges and solutions. Nat Biotechnol 24, 1377-1383.
82. Aymard, M., Gerentes, L., Valette, M., Million-Jolly, J., Lina, B., Kessler, N., Douglas, A., Cameron, K. & Hay, A. J. (1996).Variation of neuraminidase activity of influenza A H3N2 viruses isolated in MDCK cells. Options for the control of influenza III: Proceedings of the Third International Conference on Options for the Control of Influenza Amsterdam, 485-490.
83. Wagner, R., Matrosovich, M. & Klenk, H. D. (2002).Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 12, 159-166.
84. Audsley, J. M. & Tannock, G. A. (2004).The role of cell culture vaccines in the control of the next influenza pandemic. Expert Opin Biol Ther 4, 709-717.
85. Skehel, J. J. & Wiley, D. C. (2000).Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69, 531-569.
86. Taubenberger, J. K. & Morens, D. M. (2006).1918 Influenza: the mother of all pandemics. Emerg Infect Dis 12, 15-22.
87. Taubenberger, J. K., Reid, A. H., Lourens, R. M., Wang, R., Jin, G. & Fanning, T. G. (2005).Characterization of the 1918 influenza virus polymerase genes. Nature 437, 889-893.
88. Alymova, I. V., Kodihalli, S., Govorkova, E. A., Fanget, B., Gerdil, C. & Webster, R. G. (1998).Immunogenicity and protective efficacy in mice of influenza B virus vaccines grown in mammalian cells or embryonated chicken eggs. J Virol 72, 4472-4477.
89. Poon, L. L., Pritlove, D. C., Sharps, J. & Brownlee, G. G. (1998).The RNA polymerase of influenza virus, bound to the 5' end of virion RNA, acts in cis to polyadenylate mRNA. J Virol 72, 8214-8219.
90. Lu, B., Zhou, H., Ye, D., Kemble, G. & Jin, H. (2005).Improvement of influenza A/Fujian/411/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics. J Virol 79, 6763-6771.
91. Mitnaul, L. J., Matrosovich, M. N., Castrucci, M. R., Tuzikov, A. B., Bovin, N. V., Kobasa, D. & Kawaoka, Y. (2000).Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 74, 6015-6020.
92. Wagner, R., Wolff, T., Herwig, A., Pleschka, S. & Klenk, H. D. (2000).Interdependence of hemagglutinin glycosylation and neuraminidase as regulators of influenza virus growth: a study by reverse genetics. J Virol 74, 6316-6323.
93. Gomez-Puertas, P., Albo, C., Perez-Pastrana, E., Vivo, A. & Portela, A. (2000).Influenza virus matrix protein is the major driving force in virus budding. J Virol 74, 11538-11547.
94. O'Neill, R. E., Talon, J. & Palese, P. (1998).The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J 17, 288-296.
95. Regan, J. F., Liang, Y. & Parslow, T. G. (2006).Defective assembly of influenza A virus due to a mutation in the polymerase subunit PA. J Virol 80, 252-261.
96. Nobusawa, E. & Sato, K. (2006).Comparison of the mutation rates of human influenza A and B viruses. J Virol 80, 3675-3678.
97. Hara, K., Schmidt, F. I., Crow, M. & Brownlee, G. G. (2006).Amino acid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability, endonuclease activity, cap binding, and virion RNA promoter binding. J Virol 80, 7789-7798.
98. Zamarin, D., Ortigoza, M. B. & Palese, P. (2006).Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 80, 7976-7983.
99. Bottcher, E., Matrosovich, T., Beyerle, M., Klenk, H. D., Garten, W. & Matrosovich, M. (2006).Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80, 9896-9898.
100. Ohuchi, M., Ohuchi, R., Feldmann, A. & Klenk, H. D. (1997).Regulation of receptor binding affinity of influenza virus hemagglutinin by its carbohydrate moiety. J Virol 71, 8377-8384.
101. Castrucci, M. R. & Kawaoka, Y. (1993).Biologic importance of neuraminidase stalk length in influenza A virus. J Virol 67, 759-764.
102. Shu, L. L., Bean, W. J. & Webster, R. G. (1993).Analysis of the evolution and variation of the human influenza A virus nucleoprotein gene from 1933 to 1990. J Virol 67, 2723-2729.
103. Bean, W. J., Schell, M., Katz, J., Kawaoka, Y., Naeve, C., Gorman, O. & Webster, R. G. (1992).Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 66, 1129-1138.
104. Luo, G. X., Luytjes, W., Enami, M. & Palese, P. (1991).The polyadenylation signal of influenza virus RNA involves a stretch of uridines followed by the RNA duplex of the panhandle structure. J Virol 65, 2861-2867.
105. Parvin, J. D., Palese, P., Honda, A., Ishihama, A. & Krystal, M. (1989).Promoter analysis of influenza virus RNA polymerase. J Virol 63, 5142-5152.
106. Snyder, M. H., Buckler-White, A. J., London, W. T., Tierney, E. L. & Murphy, B. R. (1987).The avian influenza virus nucleoprotein gene and a specific constellation of avian and human virus polymerase genes each specify attenuation of avian-human influenza A/Pintail/79 reassortant viruses for monkeys. J Virol 61, 2857-2863.
107. Murakami, S., Horimoto, T., Mai, l. Q., Nidom, C. A., Chen, H., Muramoto, Y., Yamada, S., Iwasa, A., Iwatsuki-Horimoto, K., Shimojima, M., Iwata, A. & Kawaoka, Y. (2008).Growth determinants for H5N1 influenza vaccine seed viruses in MDCK cells. J Virol 82, 10502-10509.
108. Meguro, H., Bryant, J. D., Torrence, A. E. & Wright, P. F. (1979).Canine kidney cell line for isolation of respiratory viruses. J Clin Microbiol 9, 175-179.
109. Marcus, P. I., Ngunjiri, J. M. & Sekellick, M. J. (2009).Dynamics of biologically active subpopulations of influenza virus: plaque-forming, noninfectious cell-killing, and defective interfering particles. J Virol 83, 8122-8130.
110. Wang, C. C., Chen, J. R., Tseng, Y. C., Hsu, C. H., Hung, Y. F., Chen, S. W., Chen, C. M., Khoo, K. H., Cheng, T. J., Cheng, Y. S., Jan, J. T., Wu, C. Y., Ma, C. & Wong, C. H. (2009).Glycans on influenza hemagglutinin affect receptor binding and immune response. Proc Natl Acad Sci U S A 106, 18137-18142.
111. Suphaphiphat, P., Keiner, B., Trusheim, H., Crotta, S., Tuccino, A. B., Zhang, P., Dormitzer, P. R., Mason, P. W. & Franti, M. (2010).Human RNA Polymerase I-Driven Reverse Genetics for Influenza A Virus in Canine Cells. J Virol.
112. Neumann, G., Noda, T. & Kawaoka, Y. (2009).Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459, 931-939.
113. Matrosovich, M. N., Matrosovich, T. Y., Gray, T., Roberts, N. A. & Klenk, H. D. (2004).Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci U S A 101, 4620-4624.
114. Burleigh, L. M., Calder, L. J., Skehel, J. J. & Steinhauer, D. A. (2005).Influenza a viruses with mutations in the m1 helix six domain display a wide variety of morphological phenotypes. J Virol 79, 1262- 1270.
115. Odagiri, T. & Tobita, K. (1990).Mutation in NS2, a nonstructural protein of influenza A virus, extragenically causes aberrant replication and expression of the PA gene and leads to generation of defective interfering particles. Proc Natl Acad Sci U S A 87, 5988-5992.
116. Stieneke-Grober, A., Vey, M., Angliker, H., Shaw, E., Thomas, G., Roberts, C., Klenk, H. D. & Garten, W. (1992).Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 11, 2407-2414.
117. Yasuda, J., Nakada, S., Kato, A., Toyoda, T. & Ishihama, A. (1993).Molecular assembly of influenza virus: association of the NS2 protein with virion matrix. Virology 196, 249-255.
118. Taubenberger, J. K., Reid, A. H., Krafft, A. E., Bijwaard, K. E. & Fanning, T. G. (1997).Initial genetic characterization of the 1918 "Spanish" influenza virus. Science 275, 1793-1796.
119. Zamarin, D., Garcia-Sastre, A., Xiao, X., Wang, R. & Palese, P. (2005).Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 1, e4.
120. Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R. & Ludwig, S. (2001).Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 3, 301-305.

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