Frontiers in Biology

, Volume 6, Issue 6, pp 446–461 | Cite as

Molecular mechanisms of transcription and replication of the influenza A virus genome

Review

Abstract

Influenza Avirus is one of the major pathogens that pose a large threat to human health worldwide and has caused pandemics. Influenza A virus is the Orthomyxoviridae prototype, and has 8 segmented negative-sense single-stranded RNA (vRNA) as its genome. Influenza virus RNA polymerase (RdRp) consists of three subunits PB2, PB1 and PA, and catalyzes both transcription and replication. Recently, intensive biochemical and structural analysis of its RdRp has been performed. In this paper, we review the details from the biochemical analysis of the purified influenza virus RdRp and the classical ribonucleoprotein complex, as well as piece together their structures to form an overall picture.

Keywords

influenza virus RNA polymerase ribonucleoprotein complex transcription replication 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Almond J W (1977). A single gene determines the host range of influenza virus. Nature, 270(5638): 617–618PubMedCrossRefGoogle Scholar
  2. Area E, Martín-Benito J, Gastaminza P, Torreira E, Valpuesta J M, Carrascosa J L, Ortín J (2004). 3D structure of the influenza virus polymerase complex: localization of subunit domains. Proc Natl Acad Sci USA, 101(1): 308–313PubMedCrossRefGoogle Scholar
  3. Argos P (1988). A sequence motif in many polymerases. Nucleic Acids Res, 16(21): 9909–9916PubMedCrossRefGoogle Scholar
  4. Ball L A (2007). Virus replication strategies, 5th ed. Lippincott Williams & WilkinsGoogle Scholar
  5. Baudin F, Bach C, Cusack S, Ruigrok RW (1994). Structure of influenza virus RNP. I. Influenza virus nucleoprotein melts secondary structure in panhandle RNA and exposes the bases to the solvent. EMBO J, 13(13): 3158–3165Google Scholar
  6. Beaton A R, Krug R M (1981). Selected host cell capped RNA fragments prime influenza viral RNA transcription in vivo. Nucleic Acids Res, 9(17): 4423–4436PubMedCrossRefGoogle Scholar
  7. 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 USA, 83(17): 6282–6286PubMedCrossRefGoogle Scholar
  8. Beigel J, Bray M (2008). Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res, 78(1): 91–102PubMedCrossRefGoogle Scholar
  9. Biswas S K, Nayak D P (1994). Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J Virol, 68(3): 1819–1826PubMedGoogle Scholar
  10. Blaas D, Patzelt E, Kuechler E (1982a). Cap-recognizing protein of influenza virus. Virology, 116(1): 339–348PubMedCrossRefGoogle Scholar
  11. Blaas D, Patzelt E, Kuechler E (1982b). Identification of the cap binding protein of influenza virus. Nucleic Acids Res, 10(15): 4803–4812PubMedCrossRefGoogle Scholar
  12. Bouloy M, Plotch S J, Krug R M (1978). Globin mRNAs are primers for the transcription of influenza viral RNA in vitro. Proc Natl Acad Sci USA, 75(10): 4886–4890PubMedCrossRefGoogle Scholar
  13. Bouloy M, Plotch S J, Krug RM (1980). Both the 7-methyl and the 2′-Omethyl groups in the cap of mRNA strongly influence its ability to act as primer for influenza virus RNA transcription. Proc Natl Acad Sci USA, 77(7): 3952–3956PubMedCrossRefGoogle Scholar
  14. Bullido R, Gómez-Puertas P, Albo C, Portela A (2000). Several protein regions contribute to determine the nuclear and cytoplasmic localization of the influenza A virus nucleoprotein. J Gen Virol, 81(Pt 1): 135–142PubMedGoogle Scholar
  15. Chan A Y, Vreede F T, Smith M, Engelhardt O G, Fodor E (2006). Influenza virus inhibits RNA polymerase II elongation. Virology, 351(1): 210–217PubMedCrossRefGoogle Scholar
  16. Chen GW, Chang S C, Mok C K, Lo Y L, Kung Y N, Huang J H, Shih Y H, Wang J Y, Chiang C, Chen C J, Shih S R (2006). Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis, 12(9): 1353–1360PubMedCrossRefGoogle Scholar
  17. Chung T D, Cianci C, Hagen M, Terry B, Matthews J T, Krystal M, Colonno R J (1994). Biochemical studies on capped RNA primers identify a class of oligonucleotide inhibitors of the influenza virus RNA polymerase. Proc Natl Acad Sci USA, 91(6): 2372–2376PubMedCrossRefGoogle Scholar
  18. Coloma R, Valpuesta J M, Arranz R, Carrascosa J L, Ortín J, Martín-Benito J (2009). The structure of a biologically active influenza virus ribonucleoprotein complex. PLoS Pathog, 5(6): e1000491PubMedCrossRefGoogle Scholar
  19. Crépin T, Dias A, Palencia A, Swale C, Cusack S, Ruigrok R W (2010). Mutational and metal binding analysis of the endonuclease domain of the influenza virus polymerase PA subunit. J Virol, 84(18): 9096–9104PubMedCrossRefGoogle Scholar
  20. Cros J F, García-Sastre A, Palese P (2005). An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein. Traffic, 6(3): 205–213PubMedCrossRefGoogle Scholar
  21. Deng T, Sharps J, Fodor E, Brownlee G G (2005). In vitro assembly of PB2 with a PB1-PA dimer supports a new model of assembly of influenza A virus polymerase subunits into a functional trimeric complex. J Virol, 79(13): 8669–8674PubMedCrossRefGoogle Scholar
  22. Deng T, Engelhardt O G, Thomas B, Akoulitchev A V, Brownlee G G, Fodor E (2006a). Role of ran binding protein 5 in nuclear import and assembly of the influenza virus RNA polymerase complex. J Virol, 80(24): 11911–11919PubMedCrossRefGoogle Scholar
  23. Deng T, Sharps J L, Brownlee G G (2006b). Role of the influenza virus heterotrimeric RNA polymerase complex in the initiation of replication. J Gen Virol, 87(Pt 11): 3373–3377PubMedCrossRefGoogle Scholar
  24. Deng T, Vreede F T, Brownlee G G (2006c). Different de novo initiation strategies are used by influenza virus RNA polymerase on its Crna and viral RNA promoters during viral RNA replication. J Virol, 80(5): 2337–2348PubMedCrossRefGoogle Scholar
  25. Deyde V M, Xu X, Bright R A, Shaw M, Smith C B, Zhang Y, Shu Y, Gubareva L V, Cox N J, Klimov A I (2007). Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis, 196(2): 249–257PubMedCrossRefGoogle Scholar
  26. Dias A, Bouvier D, Crépin T, McCarthy A A, Hart D J, Baudin F, Cusack S, Ruigrok R W (2009). The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature, 458(7240): 914–918PubMedCrossRefGoogle Scholar
  27. Duan S, Boltz D A, Seiler P, Li J, Bragstad K, Nielsen L P, Webby R J, Webster R G, Govorkova E A (2010). Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets. PLoS Pathog, 6(7): e1001022PubMedCrossRefGoogle Scholar
  28. Duijsings D, Kormelink R, Goldbach R (2001). In vivo analysis of the TSWV cap-snatching mechanism: single base complementarity and primer length requirements. EMBO J, 20(10): 2545–2552PubMedCrossRefGoogle Scholar
  29. Engelhardt O G, Smith M, Fodor E (2005). Association of the influenza A virus RNA-dependent RNA polymerase with cellular RNA polymerase II. J Virol, 79(9): 5812–5818PubMedCrossRefGoogle Scholar
  30. Fechter P, Mingay L, Sharps J, Chambers A, Fodor E, Brownlee G G (2003). Two aromatic residues in the PB2 subunit of influenza A RNA polymerase are crucial for cap binding. J Biol Chem, 278(22): 20381–20388PubMedCrossRefGoogle Scholar
  31. Flick R, Hobom G (1999). Interaction of influenza virus polymerase with viral RNA in the ‘corkscrew’ conformation. J Gen Virol, 80(Pt 10): 2565–2572PubMedGoogle Scholar
  32. Fodor E, Brownlee G (2002). Influenza virus replication. In: Potter C, ed. Influenza. Elsevier, Amsterdom, pp. 1–29CrossRefGoogle Scholar
  33. Fodor E, Mikulasova A, Mingay L J, Poon L L, Brownlee G G (2000). Messenger RNAs that are not synthesized by RNA polymerase II can be 3′ end cleaved and polyadenylated. EMBO Rep, 1(6): 513–518PubMedGoogle Scholar
  34. Fodor E, Palese P, Brownlee G G, García-Sastre A (1998). Attenuation of influenza A virus mRNA levels by promoter mutations. J Virol, 72(8): 6283–6290PubMedGoogle Scholar
  35. Fodor E, Pritlove D C, Brownlee G G (1994). The influenza virus panhandle is involved in the initiation of transcription. J Virol, 68(6): 4092–4096PubMedGoogle Scholar
  36. Fodor E, Smith M (2004). The PA subunit is required for efficient nuclear accumulation of the PB1 subunit of the influenza A virus RNA polymerase complex. J Virol, 78(17): 9144–9153PubMedCrossRefGoogle Scholar
  37. Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Watanabe Y, Narita H, Shiraki K (2002). In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother, 46(4): 977–981PubMedCrossRefGoogle Scholar
  38. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K (2005). Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother, 49(3): 981–986PubMedCrossRefGoogle Scholar
  39. 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 USA, 102(51): 18590–18595PubMedCrossRefGoogle Scholar
  40. Gabriel G, Herwig A, Klenk H D (2008). Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus. PLoS Pathog, 4(2): e11PubMedCrossRefGoogle Scholar
  41. Garcin D, Kolakofsky D (1992). Tacaribe arenavirus RNA synthesis in vitro is primer dependent and suggests an unusual model for the initiation of genome replication. J Virol, 66(3): 1370–1376PubMedGoogle Scholar
  42. Garcin D, Lezzi M, Dobbs M, Elliott R M, Schmaljohn C, Kang C Y, Kolakofsky D (1995). The 5′ ends of Hantaan virus (Bunyaviridae) RNAs suggest a prime-and-realign mechanism for the initiation of RNA synthesis. J Virol, 69(9): 5754–5762PubMedGoogle Scholar
  43. González S, Zürcher T, Ortín J (1996). Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: a model for the viral RNA polymerase structure. Nucleic Acids Res, 24(22): 4456–4463PubMedCrossRefGoogle Scholar
  44. 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(5): 500–506PubMedCrossRefGoogle Scholar
  45. Gutiérrez R A, Naughtin M J, Horm S V, San S, Buchy P (2009). A(H5N1) virus evolution in South East Asia. Viruses, 1(3): 335–361PubMedCrossRefGoogle Scholar
  46. Hagen M, Chung T D, Butcher J A, Krystal M (1994). Recombinant influenza virus polymerase: requirement of both 5′ and 3′ viral ends for endonuclease activity. J Virol, 68(3): 1509–1515PubMedGoogle Scholar
  47. Hankins R W, Nagata K, Bucher D J, Popple S, Ishihama A (1989). Monoclonal antibody analysis of influenza virus matrix protein epitopes involved in transcription inhibition. Virus Genes, 3(2): 111–126PubMedCrossRefGoogle Scholar
  48. Hao L, Sakurai A, Watanabe T, Sorensen E, Nidom C A, Newton M A, Ahlquist P, Kawaoka Y (2008). Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature, 454(7206): 890–893PubMedCrossRefGoogle Scholar
  49. Hatta M, Gao P, Halfmann P, Kawaoka Y (2001). Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science, 293(5536): 1840–1842PubMedCrossRefGoogle Scholar
  50. Hauge S H, Dudman S, Borgen K, Lackenby A, Hungnes O (2009). Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007–08. Emerg Infect Dis, 15: 155–162PubMedCrossRefGoogle Scholar
  51. Hayden F (2009). Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis, 48(Suppl 1): S3–S13PubMedCrossRefGoogle Scholar
  52. He X, Zhou J, Bartlam M, Zhang R, Ma J, Lou Z, Li X, Li J, Joachimiak A, Zeng Z, Ge R, Rao Z, Liu Y (2008). Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus. Nature, 454(7208): 1123–1126PubMedCrossRefGoogle Scholar
  53. Herfst S, Chutinimitkul S, Ye J, de Wit E, Munster V J, Schrauwen E J, Bestebroer T M, Jonges M, Meijer A, Koopmans M, Rimmelzwaan G F, Osterhaus A D, Perez D R, Fouchier R A (2010). Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. J Virol, 84(8): 3752–3758PubMedCrossRefGoogle Scholar
  54. Honda A, Endo A, Mizumoto K, Ishihama A (2001). Differential roles of viral RNA and cRNA in functional modulation of the influenza virus RNA polymerase. J Biol Chem, 276(33): 31179–31185PubMedCrossRefGoogle Scholar
  55. Honda A, Mizumoto K, Ishihama A (1999). Two separate sequences of PB2 subunit constitute the RNA cap-binding site of influenza virus RNA polymerase. Genes Cells, 4(8): 475–485PubMedCrossRefGoogle Scholar
  56. Honda A, Mizumoto K, Ishihama A (2002). Minimum molecular architectures for transcription and replication of the influenza virus. Proc Natl Acad Sci USA, 99(20): 13166–13171PubMedCrossRefGoogle Scholar
  57. Honda A, Mukaigawa J, Yokoiyama A, Kato A, Ueda S, Nagata K, Krystal M, Nayak D P, Ishihama A (1990). Purification and molecular structure of RNA polymerase from influenza virus A/PR8. J Biochem, 107(4): 624–628PubMedGoogle Scholar
  58. Honda A, Okamoto T, Ishihama A (2007). Host factor Ebp1: selective inhibitor of influenza virus transcriptase. Genes Cells, 12(2): 133–142PubMedCrossRefGoogle Scholar
  59. Honda A, Uéda K, Nagata K, Ishihama A (1988). RNA polymerase of influenza virus: role of NP in RNA chain elongation. J Biochem, 104(6): 1021–1026PubMedGoogle Scholar
  60. Huarte M, Sanz-Ezquerro J J, Roncal F, Ortín J, Nieto A (2001). PA subunit from influenza virus polymerase complex interacts with a cellular protein with homology to a family of transcriptional activators. J Virol, 75(18): 8597–8604PubMedCrossRefGoogle Scholar
  61. Huiet L, Feldstein P A, Tsai J H, Falk BW(1993). The maize stripe virus major noncapsid protein messenger RNA transcripts contain heterogeneous leader sequences at their 5′ termini. Virology, 197(2): 808–812PubMedCrossRefGoogle Scholar
  62. Hurt A C, Ho H T, Barr I (2006). Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors. Expert Rev Anti Infect Ther, 4(5): 795–805PubMedCrossRefGoogle Scholar
  63. Ishihama A, Nagata K (1988). Viral RNA polymerases. CRC Crit Rev Biochem, 23(1): 27–76PubMedCrossRefGoogle Scholar
  64. Jiang H, Zhang S, Wang Q, Wang J, Geng L, Toyoda T (2010). Influenza virus genome C4 promoter/origin attenuates its transcription and replication activity by the low polymerase recognition activity. Virology, 408(2): 190–196PubMedCrossRefGoogle Scholar
  65. Jin H, Elliott R M (1993a). Characterization of Bunyamwera virus S RNA that is transcribed and replicated by the L protein expressed from recombinant vaccinia virus. J Virol, 67(3): 1396–1404PubMedGoogle Scholar
  66. Jin H, Elliott R M (1993b). Non-viral sequences at the 5′ ends of Dugbe nairovirus S mRNAs. J Gen Virol, 74(Pt 10): 2293–2297PubMedCrossRefGoogle Scholar
  67. Kao C C, Singh P, Ecker D J (2001). De novo initiation of viral RNA-dependent RNA synthesis. Virology, 287(2): 251–260PubMedCrossRefGoogle Scholar
  68. Kao C C, Sun J H (1996). Initiation of minus-strand RNA synthesis by the brome mosaicvirus RNA-dependent RNA polymerase: use of oligoribonucleotide primers. J Virol, 70(10): 6826–6830PubMedGoogle Scholar
  69. Kao R Y, Yang D, Lau L S, Tsui W H, Hu L, Dai J, Chan M P, Chan C M, Wang P, Zheng B J, Sun J, Huang J D, Madar J, Chen G, Chen H, Guan Y, Yuen K Y (2010). Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol, 28(6): 600–605PubMedCrossRefGoogle Scholar
  70. Karlas A, Machuy N, Shin Y, Pleissner K P, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie L A, Hess S, Mäurer A P, Müller E, Wolff T, Rudel T, Meyer T F (2010). Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature, 463(7282): 818–822PubMedCrossRefGoogle Scholar
  71. Kashiwagi T, Leung B W, Deng T, Chen H, Brownlee G G (2009). The N-terminal region of the PA subunit of the RNA polymerase of influenza A/HongKong/156/97 (H5N1) influences promoter binding. PLoS One, 4(5): e5473PubMedCrossRefGoogle Scholar
  72. Kawaguchi A, Nagata K (2007). De novo replication of the influenza virus RNA genome is regulated by DNA replicative helicase, MCM. EMBO J, 26(21): 4566–4575PubMedCrossRefGoogle Scholar
  73. Kawakami K, Mizumoto K, Ishihama A (1983). RNA polymerase of influenza virus. IV. Catalytic properties of the capped RNA endonuclease associated with the RNA polymerase. Nucleic Acids Res, 11(11): 3637–3649PubMedCrossRefGoogle Scholar
  74. Kiso M, Shinya K, Shimojima M, Takano R, Takahashi K, Katsura H, Kakugawa S, Le M T, Yamashita M, Furuta Y, Ozawa M, Kawaoka Y (2010). Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses. PLoS Pathog, 6(8): e1001079PubMedCrossRefGoogle Scholar
  75. Kobayashi M, Toyoda T, Ishihama A (1996). Influenza virus PB1 protein is the minimal and essential subunit of RNA polymerase. Arch Virol, 141(3–4): 525–539PubMedCrossRefGoogle Scholar
  76. König R, Stertz S, Zhou Y, Inoue A, Hoffmann H H, Bhattacharyya S, Alamares J G, Tscherne D M, Ortigoza M B, Liang Y, Gao Q, Andrews S E, Bandyopadhyay S, De Jesus P, Tu B P, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, García-Sastre A, Young J A, Palese P, Shaw M L, Chanda S K (2010). Human host factors required for influenza virus replication. Nature, 463(7282): 813–817PubMedCrossRefGoogle Scholar
  77. Kormelink R, van Poelwijk F, Peters D, Goldbach R (1992). Non-viral heterogeneous sequences at the 5′ ends of tomato spotted wilt virus mRNAs. J Gen Virol, 73(8): 2125–2128PubMedCrossRefGoogle Scholar
  78. Kuzuhara T, Kise D, Yoshida H, Horita T, Murazaki Y, Nishimura A, Echigo N, Utsunomiya H, Tsuge H (2009a). Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J Biol Chem, 284(22): 6855–6860PubMedGoogle Scholar
  79. Kuzuhara T, Kise D, Yoshida H, Horita T, Murazaki Y, Nishimura A, Echigo N, Utsunomiya H, Tsuge H (2009b). Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J Biol Chem, 284(11): 6855–6860PubMedCrossRefGoogle Scholar
  80. Lackenby A, Thompson C I, Democratis J (2008). The potential impact of neuraminidase inhibitor resistant influenza. Curr Opin Infect Dis, 21(6): 626–638PubMedCrossRefGoogle Scholar
  81. Leahy MB, Dobbyn H C, Brownlee G G (2001a). Hairpin loop structure in the 3′ arm of the influenza A virus virion RNA promoter is required for endonuclease activity. J Virol, 75(15): 7042–7049PubMedCrossRefGoogle Scholar
  82. Leahy M B, Pritlove D C, Poon L L, Brownlee G G (2001b). Mutagenic analysis of the 5′ arm of the influenza A virus virion RNA promoter defines the sequence requirements for endonuclease activity. J Virol, 75(1): 134–142PubMedCrossRefGoogle Scholar
  83. Li M L, Rao P, Krug R M (2001). The active sites of the influenza cap-dependent endonuclease are on different polymerase subunits. EMBO J, 20(8): 2078–2086PubMedCrossRefGoogle Scholar
  84. Li X, Palese P (1994). Characterization of the polyadenylation signal of influenza virus RNA. J Virol, 68(2): 1245–1249PubMedGoogle Scholar
  85. Li Z, Chen H, Jiao P, Deng G, Tian G, Li Y, Hoffmann E, Webster R G, Matsuoka Y, Yu K (2005). Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol, 79(18): 12058–12064PubMedCrossRefGoogle Scholar
  86. Luo G, Hamatake R K, Mathis D M, Racela J, Rigat K L, Lemm J, Colonno R J (2000). De novo initiation of RNA synthesis by the RNA-dependent RNA polymerase (NS5B) of hepatitis C virus. J Virol, 74(2): 851–863PubMedCrossRefGoogle Scholar
  87. 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(6): 2861–2867PubMedGoogle Scholar
  88. Mark G E, Taylor JM, Broni B, Krug RM (1979). Nuclear accumulation of influenza viral RNA transcripts and the effects of cycloheximide, actinomycin D, and alpha-amanitin. J Virol, 29(2): 744–752PubMedGoogle Scholar
  89. Martin K, Helenius A (1991). Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell, 67(1): 117–130PubMedCrossRefGoogle Scholar
  90. Massin P, van der Werf S, Naffakh N (2001). Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol, 75(11): 5398–5404PubMedCrossRefGoogle Scholar
  91. Mayer D, Molawi K, Martínez-Sobrido L, Ghanem A, Thomas S, Baginsky S, Grossmann J, García-Sastre A, Schwemmle M (2007). Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. J Proteome Res, 6(2): 672–682PubMedCrossRefGoogle Scholar
  92. Mehle A, Doudna J A (2008). An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase. Cell Host Microbe, 4(2): 111–122PubMedCrossRefGoogle Scholar
  93. Momose F, Basler C F, O’Neill R E, Iwamatsu A, Palese P, Nagata K (2001). Cellular splicing factor RAF-2p48/NPI-5/BAT1/UAP56 interacts with the influenza virus nucleoprotein and enhances viral RNA synthesis. J Virol, 75(4): 1899–1908PubMedCrossRefGoogle Scholar
  94. Momose F, Handa H, Nagata K (1996). Identification of host factors that regulate the influenza virus RNA polymerase activity. Biochimie, 78(11–12): 1103–1108PubMedCrossRefGoogle Scholar
  95. Momose F, Naito T, Yano K, Sugimoto S, Morikawa Y, Nagata K (2002). Identification of Hsp90 as a stimulatory host factor involved in influenza virus RNA synthesis. J Biol Chem, 277(47): 45306–45314PubMedCrossRefGoogle Scholar
  96. Monsalvo A C, Batalle J P, Lopez M F, Krause J C, Klemenc J, Hernandez J Z, Maskin B, Bugna J, Rubinstein C, Aguilar L, Dalurzo L, Libster R, Savy V, Baumeister E, Aguilar L, Cabral G, Font J, Solari L, Weller K P, Johnson J, Echavarria M, Edwards K M, Chappell J D, Crowe J E Jr, Williams J V, Melendi G A, Polack F P (2011). Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med, 17(2): 195–199PubMedCrossRefGoogle Scholar
  97. Moscona A (2009). Global transmission of oseltamivir-resistant influenza. N Engl J Med, 360(10): 953–956PubMedCrossRefGoogle Scholar
  98. Moss R B, Davey R T, Steigbigel R T, Fang F (2010). Targeting pandemic influenza: a primer on influenza antivirals and drug resistance. J Antimicrob Chemother, 65(6): 1086–1093PubMedCrossRefGoogle Scholar
  99. Nagata K, Kawaguchi A, Naito T (2008). Host factors for replication and transcription of the influenza virus genome. Rev Med Virol, 18(4): 247–260PubMedCrossRefGoogle Scholar
  100. Naito T, Kiyasu Y, Sugiyama K, Kimura A, Nakano R, Matsukage A, Nagata K (2007a). An influenza virus replicon system in yeast identified Tat-SF1 as a stimulatory host factor for viral RNA synthesis. Proc Natl Acad Sci USA, 104(46): 18235–18240PubMedCrossRefGoogle Scholar
  101. Naito T, Momose F, Kawaguchi A, Nagata K (2007b). Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol, 81(3): 1339–1349PubMedCrossRefGoogle Scholar
  102. Nakagawa Y, Oda K, Nakada S (1996). The PB1 subunit alone can catalyze cRNA synthesis, and the PA subunit in addition to the PB1 subunit is required for viral RNA synthesis in replication of the influenza virus genome. J Virol, 70(9): 6390–6394PubMedGoogle Scholar
  103. Neumann G, Castrucci M R, Kawaoka Y (1997). Nuclear import and export of influenza virus nucleoprotein. J Virol, 71(12): 9690–9700PubMedGoogle Scholar
  104. Neumann G, Hobom G (1995). Mutational analysis of influenza virus promoter elements in vivo. J Gen Virol, 76(7): 1709–1717PubMedCrossRefGoogle Scholar
  105. Newcomb L L, Kuo R L, Ye Q, Jiang Y, Tao Y J, Krug R M (2009). Interaction of the influenza a virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication. J Virol, 83(1): 29–36PubMedCrossRefGoogle Scholar
  106. O’Neill R E, Jaskunas R, Blobel G, Palese P, Moroianu J (1995). Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. J Biol Chem, 270(39): 22701–22704PubMedCrossRefGoogle Scholar
  107. O’Neill R E, Palese P (1995). NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein. Virology, 206(1): 116–125PubMedCrossRefGoogle Scholar
  108. Obayashi E, Yoshida H, Kawai F, Shibayama N, Kawaguchi A, Nagata K, Tame J R, Park S Y (2008). The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature, 454(7208): 1127–1131PubMedCrossRefGoogle Scholar
  109. Oberg B (2006). Rational design of polymerase inhibitors as antiviral drugs. Antiviral Res, 71(2–3): 90–95PubMedCrossRefGoogle Scholar
  110. Ohtsu Y, Honda Y, Sakata Y, Kato H, Toyoda T (2002). Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol Immunol, 46(3): 167–175PubMedGoogle Scholar
  111. Ortega J, Martín-Benito J, Zürcher T, Valpuesta J M, Carrascosa J L, Ortín J (2000). Ultrastructural and functional analyses of recombinant influenza virus ribonucleoproteins suggest dimerization of nucleoprotein during virus amplification. J Virol, 74(1): 156–163PubMedCrossRefGoogle Scholar
  112. Palese P, Shaw M L (2007). Orthomyxoviridae: the Viruses and Their Replication, 5th ed. Lippincott Williams & WilkinsGoogle Scholar
  113. Paul A V, Rieder E, Kim D W, van Boom J H, Wimmer E (2000). Identification of an RNA hairpin in poliovirus RNA that serves as the primary template in the in vitro uridylylation of VPg. J Virol, 74(22): 10359–10370PubMedCrossRefGoogle Scholar
  114. Pérez D R, Donis R O (1995). A 48-amino-acid region of influenza A virus PB1 protein is sufficient for complex formation with PA. J Virol, 69(11): 6932–6939PubMedGoogle Scholar
  115. Pérez-González A, Rodriguez A, Huarte M, Salanueva I J, Nieto A (2006). hCLE/CGI-99, a human protein that interacts with the influenza virus polymerase, is a mRNA transcription modulator. J Mol Biol, 362(5): 887–900PubMedCrossRefGoogle Scholar
  116. Plotch S J, Bouloy M, Ulmanen I, Krug R M (1981). A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell, 23(3): 847–858PubMedCrossRefGoogle Scholar
  117. Plotch S J, Krug R M (1977). Influenza virion transcriptase: synthesis in vitro of large, polyadenylic acid-containing complementary RNA. J Virol, 21(1): 24–34PubMedGoogle Scholar
  118. Plotch S J, Krug R M (1978). Segments of influenza virus complementary RNA synthesized in vitro. J Virol, 25(2): 579–586PubMedGoogle Scholar
  119. Plotkin J B, Dushoff J, Levin S A (2002). Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc Natl Acad Sci USA, 99(9): 6263–6268PubMedCrossRefGoogle Scholar
  120. Poole E L, Medcalf L, Elton D, Digard P (2007). Evidence that the C-terminal PB2-binding region of the influenza A virus PB1 protein is a discrete α-helical domain. FEBS Lett, 581(27): 5300–5306PubMedCrossRefGoogle Scholar
  121. Poon L L, Fodor E, Brownlee G G (2000). Polyuridylated mRNA synthesized by a recombinant influenza virus is defective in nuclear export. J Virol, 74(1): 418–427PubMedCrossRefGoogle Scholar
  122. Poon L L, Pritlove D C, Fodor E, Brownlee G G (1999). Direct evidence that the poly(A) tail of influenza A virus mRNA is synthesized by reiterative copying of a U track in the virion RNA template. J Virol, 73(4): 3473–3476PubMedGoogle Scholar
  123. 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(10): 8214–8219PubMedGoogle Scholar
  124. Pritlove D C, Poon L L, Devenish L J, Leahy M B, Brownlee G G (1999). A hairpin loop at the 5′ end of influenza A virus virion RNA is required for synthesis of poly(A)+ mRNA in vitro. J Virol, 73(3): 2109–2114PubMedGoogle Scholar
  125. Pritlove D C, Poon L L, Fodor E, Sharps J, Brownlee G G (1998). Polyadenylation of influenza virus mRNA transcribed in vitro from model virion RNA templates: requirement for 5′ conserved sequences. J Virol, 72(2): 1280–1286PubMedGoogle Scholar
  126. Rao P, Yuan W, Krug R M (2003). Crucial role of CA cleavage sites in the cap-snatching mechanism for initiating viral mRNA synthesis. EMBO J, 22(5): 1188–1198PubMedCrossRefGoogle Scholar
  127. Resa-Infante P, Jorba N, Zamarreño N, Fernández Y, Juárez S, Ortín J (2008). The host-dependent interaction of alpha-importins with influenza PB2 polymerase subunit is required for virus RNA replication. PLoS ONE, 3(12): e3904PubMedCrossRefGoogle Scholar
  128. Robertson J S, Schubert M, Lazzarini R A (1981). Polyadenylation sites for influenza virus mRNA. J Virol, 38(1): 157–163PubMedGoogle Scholar
  129. Seong B L, Kobayashi M, Nagata K, Brownlee G G, Ishihama A (1992). Comparison of two reconstituted systems for in vitro transcription and replication of influenza virus. J Biochem, 111(4): 496–499PubMedGoogle Scholar
  130. Shapiro G I, Krug R M (1988). Influenza virus RNA replication in vitro: synthesis of viral template RNAs and virion RNAs in the absence of an added primer. J Virol, 62(7): 2285–2290PubMedGoogle Scholar
  131. Shaw M W, Lamb R A (1984). A specific sub-set of host-cell mRNAs prime influenza virus mRNA synthesis. Virus Res, 1(6): 455–467PubMedCrossRefGoogle Scholar
  132. Su C Y, Cheng T J, Lin M I, Wang S Y, Huang W I, Lin-Chu S Y, Chen Y H, Wu C Y, Lai MM, Cheng WC, Wu Y T, Tsai MD, Cheng Y S, Wong C H (2010). High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity. Proc Natl Acad Sci USA, 107(45): 19151–19156PubMedCrossRefGoogle Scholar
  133. Subbarao E K, London W, Murphy B R (1993). A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol, 67(4): 1761–1764PubMedGoogle Scholar
  134. Sugiyama K, Obayashi E, Kawaguchi A, Suzuki Y, Tame J R, Nagata K, Park S Y (2009). Structural insight into the essential PB1-PB2 subunit contact of the influenza virus RNA polymerase. EMBO J, 28(12): 1803–1811PubMedCrossRefGoogle Scholar
  135. Tarendeau F, Boudet J, Guilligay D, Mas P J, Bougault C M, Boulo S, Baudin F, Ruigrok R W, Daigle N, Ellenberg J, Cusack S, Simorre J P, Hart D J (2007). Structure and nuclear import function of the Cterminal domain of influenza virus polymerase PB2 subunit. Nat Struct Mol Biol, 14(3): 229–233PubMedCrossRefGoogle Scholar
  136. Testa D, Banerjee A K (1979). Initiation of RNA synthesis in vitro by vesicular stomatitis virus. Role of ATP. J Biol Chem, 254(6): 2053–2058Google Scholar
  137. Torreira E, Schoehn G, Fernández Y, Jorba N, Ruigrok R W, Cusack S, Ortín J, Llorca O (2007). Three-dimensional model for the isolated recombinant influenza virus polymerase heterotrimer. Nucleic Acids Res, 35(11): 3774–3783PubMedCrossRefGoogle Scholar
  138. Toyoda T, Adyshev D M, Kobayashi M, Iwata A, Ishihama A (1996a). Molecular assembly of the influenza virus RNA polymerase: determination of the subunit-subunit contact sites. J Gen Virol, 77(9): 2149–2157PubMedCrossRefGoogle Scholar
  139. Toyoda T, Kobayashi M, Nakada S, Ishihama A (1996b). Molecular dissection of influenza virus RNA polymerase: PB1 subunit alone is able to catalyze RNA synthesis. Virus Genes, 12(2): 155–163PubMedCrossRefGoogle Scholar
  140. Tsai C H, Lee P Y, Stollar V, Li M L (2006). Antiviral therapy targeting viral polymerase. Curr Pharm Des, 12(11): 1339–1355PubMedCrossRefGoogle Scholar
  141. Ulmanen I, Broni B, Krug R M (1983). Influenza virus temperature-sensitive cap (m7GpppNm)-dependent endonuclease. J Virol, 45(1): 27–35PubMedGoogle Scholar
  142. 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 USA, 78(12): 7355–7359PubMedCrossRefGoogle Scholar
  143. van Dijk A A, Makeyev E V, Bamford D H (2004). Initiation of viral RNA-dependent RNA polymerization. J Gen Virol, 85(5): 1077–1093PubMedCrossRefGoogle Scholar
  144. Vreede F T, Brownlee G G (2007). Influenza virion-derived viral ribonucleoproteins synthesize both mRNA and cRNA in vitro. J Virol, 81(5): 2196–2204PubMedCrossRefGoogle Scholar
  145. Vreede F T, Gifford H, Brownlee G G (2008). Role of initiating nucleoside triphosphate concentrations in the regulation of influenza virus replication and transcription. J Virol, 82(14): 6902–6910PubMedCrossRefGoogle Scholar
  146. Vreede F T, Jung T E, Brownlee G G (2004). Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. J Virol, 78(17): 9568–9572PubMedCrossRefGoogle Scholar
  147. 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(3): 1850–1856PubMedGoogle Scholar
  148. Watanabe K, Handa H, Mizumoto K, Nagata K (1996). Mechanism for inhibition of influenza virus RNA polymerase activity by matrix protein. J Virol, 70(1): 241–247PubMedGoogle Scholar
  149. Weber F, Kochs G, Gruber S, Haller O (1998). A classical bipartite nuclear localization signal on Thogoto and influenza A virus nucleoproteins. Virology, 250(1): 9–18PubMedCrossRefGoogle Scholar
  150. Webster R G, Sharp G B, Claas E C (1995). Interspecies transmission of influenza viruses. Am J Respir Crit Care Med, 152(4 Pt 2): S25–S30PubMedGoogle Scholar
  151. Wright P F, Neumann G, Kawaoka Y (2007). Orthomyxoviruses, 5th ed. Lippincott Williams & Wilkins.Google Scholar
  152. Yang Y, Rijnbrand R, Watowich S, Lemon S M (2004). Genetic evidence for an interaction between a picornaviral cis-acting RNA replication element and 3CD protein. J Biol Chem, 279(13): 12659–12667PubMedCrossRefGoogle Scholar
  153. Ye Q, Krug R M, Tao Y J (2006). The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature, 444(7122): 1078–1082PubMedCrossRefGoogle Scholar
  154. Ye Z P, Pal R, Fox J W, Wagner R R (1987). Functional and antigenic domains of the matrix (M1) protein of influenza A virus. J Virol, 61(2): 239–246PubMedGoogle Scholar
  155. 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(7240): 909–913PubMedCrossRefGoogle Scholar
  156. Zhang S, Wang J, Wang Q, Toyoda T (2010a). Internal initiation of influenza virus replication of viral RNA and complementary RNA in vitro. J Biol Chem, 285: 41194–41201PubMedCrossRefGoogle Scholar
  157. Zhang S, Weng L, Geng L, Wang J, Zhou J, Deubel V, Buchy P, Toyoda T (2010b). Biochemical and kinetic analysis of the influenza virus RNA polymerase purified from insect cells. Biochem Biophys Res Commun, 391(1): 570–574PubMedCrossRefGoogle Scholar
  158. Zhao C, Lou Z, Guo Y, Ma M, Chen Y, Liang S, Zhang L, Chen S, Li X, Liu Y, Bartlam M, Rao Z (2009). Nucleoside monophosphate complex structures of the endonuclease domain from the influenza virus polymerase PA subunit reveal the substrate binding site inside the catalytic center. J Virol, 83(18): 9024–9030PubMedCrossRefGoogle Scholar
  159. Zheng H, Lee H A, Palese P, García-Sastre A (1999). Influenza A virus RNA polymerase has the ability to stutter at the polyadenylation site of a viral RNA template during RNA replication. J Virol, 73(6): 5240–5243PubMedGoogle Scholar
  160. Zvonarjev A Y, Ghendon Y Z (1980). Influence of membrane (M) protein on influenza A virus virion transcriptase activity in vitro and its susceptibility to rimantadine. J Virol, 33(2): 583–586PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Shanghai Medical College of Fudan UniversityShanghaiChina
  2. 2.Choju Medical InstituteFukushimura HospitalToyohashi, AichiJapan
  3. 3.Infectious Disease Regulation ProjectTokyo Metropolitan Institute of Medical SciencesTokyoJapan

Personalised recommendations