Influenza Viruses: Molecular Virology

Gabriele Neumann, University of Wisconsin‐Madison, Madison, Wisconsin, USA
Yoshihiro Kawaoka, University of Tokyo, Tokyo, Wisconsin, Japan

Published online: April 2011

DOI: 10.1002/9780470015902.a0001031.pub3

Influenza viruses cause mild to potentially lethal respiratory disease. Influenza A viruses cause annual outbreaks of local scale and occasional outbreaks of global scale, as witnessed with the pandemic of 2009 that was caused by an influenza A viruses of the H1N1 subtype. Influenza B viruses also cause disease in humans, whereas influenza C viruses are not a recognised public health concern. Influenza A, B and C viruses share many similarities in their coding strategies and life cycles, but can also be distinguished by key differences. Here we summarise the molecular virology of influenza A, B and C viruses, that is the similarities and differences in coding strategies, the replication cycle and the functions of the viral proteins.

Key Concepts:

  • Influenza A, B and C viruses differ in their impact on human health.
  • Although influenza A, B and C viruses share many similarities, they differ in their coding strategies.
  • The basic functions of the viral proteins are now understood, but many questions remain about the interplay between the viral proteins, and the interplay between viral and cellular proteins.

Keywords: influenza A viruses; influenza B viruses; influenza C viruses; influenza virus proteins; influenza virus structure; influenza virus replication; haemagglutinin; neuraminidase

Figure 1. Structural features of an influenza A virion. Two glycoprotein spikes, haemagglutinin (HA) and neuraminidase (NA) and the M2 protein are embedded in a lipid bilayer derived from the host plasma membrane. The ribonucleoprotein complex (RNP) consists of viral RNA, associated with the nucleoprotein (NP) and three polymerase proteins (PA, PB1 and PB2). NS2(NEP) is associated with RNP, while the M1 protein is associated with both RNP and the viral envelope. Thus, NS1 is the only nonstructural protein of influenza A virus.
Figure 2. Coding strategies of influenza virus genes. (a) Influenza A virus NS1 and NS2 mRNAs and their coding regions. NS1 and NS2 share 10 N-terminal residues, including the initiating methionine. The reading frame of NS2 mRNA (nucleotide positions 529–861) differs from that of NS1. (b) Influenza A virus M1, M2 mRNAs and mRNA3 and their coding regions. M1 and M2 share nine N-terminal residues, including the initiating methionine; however, the reading frame of M2 mRNA (nucleotide positions 740–1004) differs from that of M1. A translation product of mRNA3 has not been found in cells. (c) Coding regions of the influenza A virus PB1 segment. Based on Kozak's rule, PB1 translation initiation may be inefficient, thereby allowing translation initiation of the PB1-F2 open reading frame by ribosomal scanning. (d) Influenza B virus RNA segment 7 open reading frames and the organisation of the open reading frames used to translate the M1 and BM2 proteins. The stop–start pentanucleotide is also illustrated. (e) Open reading frames in influenza B virus RNA segment 6, illustrating the overlapping reading frames of NB and neuraminidase (NA). The nucleotide sequence surrounding the two AUG initiation codons, in mRNA sense, is shown to the right. (f) Influenza C virus mRNAs derived from RNA segment 6. The unspliced and spliced mRNAs encode P42 and M1, respectively. Cleavage of P42 by a signal peptidase yields M1¢ and CM2. For (a)–(f), thin lines at the 5¢ and 3¢ termini of the mRNAs represent untranslated regions. The shaded or hatched areas represent different coding regions. Introns in the mRNAs are shown by V-shaped lines; filled rectangles at the 5¢ ends of mRNAs represent heterogeneous nucleotides derived from cellular RNAs that are covalently linked to viral sequences. Numbers to the right indicate the number of amino acids (aa) encoded by each open reading frame. From Cox NJ, Neumann G, Donis RO and Kawaoka Y (2005) Orthomyxoviruses: influenza. In: Collier L, Balows A and Sussman M (eds) Topley & Wilson's Microbiology and Microbial Infections, pp. 634–698. London: Arnold. Copyright Edward Arnold Publisher Ltd. Reproduced with permission of Edward Arnold.
Figure 3. Replication cycle of Influenza A virus, from binding of the virus to the host cell surface to its exit from the plasma membrane. Modified from Lamb RA, Holsinger LJ and Pinto LH (1994) The influenza A virus M2 ion channel protein and its role in the influenza virus life cycle. In: Wimmer E (ed.) Cellular Receptors for Animal Viruses, pp. 303–321. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.
close
 References
    Billharz R, Zeng H, Proll SC et al. (2009) The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways. Journal of Virology 83: 10557–10570.
    Brass AL, Huang IC, Benita Y et al. (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139: 1243–1254.
    Chakrabarti AK, Vipat VC, Mukherjee S et al. (2010) Host gene expression profiling in influenza A virus-infected lung epithelial (A549) cells: a comparative analysis between highly pathogenic and modified H5N1 viruses. Virology Journal 7: 219.
    Chen W, Calvo PA, Malide D et al. (2001) A novel influenza A virus mitochondrial protein that induces cell death. Nature Medicine 7: 1306–1312.
    Dawood FS, Jain S, Finelli L et al. (2009) Emergence of a novel swine-origin influenza A (H1N1) virus in humans. New England Journal of Medicine 360: 2605–2615.
    Dos Santos AE, Escriou N, Leclercq I, van der WS and Naffakh N (2005) The generation of recombinant influenza A viruses expressing a PB2 fusion protein requires the conservation of a packaging signal overlapping the coding and noncoding regions at the 5¢ end of the PB2 segment. Virology 341: 34–46.
    Fouchier RA, Schneeberger PM, Rozendaal FW et al. (2004) Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proceedings of the National Academy of Sciences of the USA 101: 1356–1361.
    Fujii K, Fujii Y, Noda T 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. Journal of Virology 79: 3766–3774.
    Fujii K, Ozawa M, Iwatsuki-Horimoto K et al. (2009) Incorporation of influenza A virus genome segments does not absolutely required wild-type sequences. Journal of General Virology 90: 1734–1740.
    Fujii Y, Goto H, Watanabe T, Yoshida T and Kawaoka Y (2003) Selective incorporation of influenza virus RNA segments into virions. Proceedings of the National Academy of Sciences of the USA 100: 2002–2007.
    Garten W and Klenk HD (1999) Understanding influenza virus pathogenicity. Trends in Microbiology 7: 99–100.
    Gog JR, Afonso Edos S, Dalton RM et al. (2007) Codon conservation in the influenza A virus genome defines RNA packaging signals. Nucleic Acids Research 35: 1897–1907.
    Hao L, Sakurai A, Watanabe T et al. (2008) Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454: 890–893.
    Hatta M, Gao P, Halfmann P and Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293: 1840–1842.
    Horimoto T and Kawaoka Y (2001) Pandemic threat posed by avian influenza A viruses. Clinical Microbiology Reviews 14: 129–149.
    Hutchinson EC, Curran MC, Read EK et al. (2008) Mutational analysis of cis-acting RNA signals in segment 7 of influenza A virus. Journal of Virology 82: 11689–11879.
    Jackson D, Hossain MJ, Hickman D et al. (2008) A new influenza virus virulence determinant: the NS1 protein four C-terminal residues module pathogenicity. Proceedings of the National Academy of Sciences of the USA 105: 4381–4386.
    Karlas A, Machuy N, Shin Y et al. (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463: 818–822.
    Konig R, Stertz S, Zhou Y et al. (2010) Human host factors required for influenza virus replication. Nature 463: 813–817.
    Li KS, Guan Y, Wang J et al. (2004) Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430: 209–213.
    Liang Y, Hong Y and Parslow TG (2005) Cis-acting packaging signals in the influenza virus PB1, PB2, and PA genomic RNA segments. Journal of Virology 79: 10348–10355.
    Liang Y, Huang T, Ly H et al. (2008) Mutational analyses of packaging signals in influenza virus PA, PB1, and PB2 genomic RNA segments. Journal of Virology 82: 229–236.
    Marsh GA, Hatami R and Palese P (2007) Specific residues of the influenza A virus hemagglutinin viral RNA are important for efficient packaging into budding virions. Journal of Virology 81: 9727–9736.
    Marsh GA, Rabadan R, Levine AJ et al. (2008) Highly conserved regions of influenza a virus polymerase gene segments are critical for efficient viral RNA packaging. Journal of Virology 82: 2295–2304.
    Matrosovich MN, Matrosovich TY, Gray T, Roberts NA and Klenk HD (2004) Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proceedings of the National Academy of Sciences of the USA 101: 4620–4624.
    Mayer D, Molawi K, Martinez-Sobrido L et al. (2007) Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. Journal of Proteome Research 6: 672–682.
    Mehle A and Doudna JA (2009) Adaptive strategies of the influenza virus polymerase for replication in humans. Proceedings of the National Academy of Sciences of the USA 106: 21312–21316.
    Min JY and Krug RM (2006) The primary function of RNA binding the the influenza A virus NS1 protein in infected cells: Inhibiting the 2¢-5¢ oligon (A) synthetase/RNase L pathway. Proceedings of the National Academy of Sciences of the USA 103: 7100–7105.
    Muramoto Y, Takada A, Fujii K et al. (2006) Hierarchy among viral RNA (vRNA) segments in their role in vRNA incorporation into influenza A virions. Journal of Virology 80: 2318–2325.
    Noda T, Sagara H, Yen A et al. (2006) Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature 439: 490–492.
    Obenauer JC, Denson J, Mehta PK et al. (2006) Large-scale sequence analysis of avian influenza isolates. Science 311: 1576–1580.
    Ozawa M, Fujii K, Muramoto Y et al. (2007) Contributions of two nuclear localization signals of influenza A virus nucleoprotein to viral replication. Journal of Virology 81: 30–41.
    Ozawa M, Maeda J, Iwatsuki-Horimoto K et al. (2009) Nucleotide sequence requirements at the 5¢ end of influenza A virus M RNA segment for efficient virus replication. Journal of Virology 83: 3384–3388.
    book Palese P and Shaw ML (2007) "Orthomyxoviridae: the viruses and their replication". In: Knipe DM, Howley PM, Griffin DE et al. (eds) Fields Virology, pp. 1647–1689. Philadelphia: Wolters Kluwer; Lippincott Williams & Wilkins.
    Puthavathana P, Auewarakul P, Charoenying PC et al. (2005) Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand. Journal of General Virology 86: 423–433.
    Reemers SS, Groot Koerkamp MJ, Hostege FC et al. (2009) Cellular host transcriptional responses to influenza A virus in chicken tracheal organ cultures differ from responses in vivo infected trachea. Veterinary Immunology and Immunopathology 132: 91–100.
    Rogers GN and Paulson JC (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.
    Seo SH, Hoffmann E and Webster RG (2002) Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Medicine 8: 950–954.
    Shapira SD, Gat-Viks I, Shum BO et al. (2009) A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139: 1255–1267.
    Shinya K, Ebina M, Yamada S et al. (2006) Avian flu: influenza virus receptors in the human airway. Nature 440: 435–436.
    Van Riel D, Munster VJ, de Wit E et al. (2006) H5N1 virus attachment to the lower respiratory tract. Science 312: 399.
    Vreede FT, Jung TE and Brownlee GG (2004) Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. Journal of Virology 78: 9568–9572.
    Watanabe T, Watanabe S, Noda T, Fujii Y and Kawaoka Y (2003) Exploitation of nucleic acid packaging signals to generate a novel influenza virus-based vector stably expressing two foreign genes. Journal of Virology 77: 10575–10583.
    book Wright PF, Neumann G and Kawaoka Y (2007) "Orthomyxoviruses". In: Knipe DM, Howley PM, Griffin DE et al. (eds) Fields Virology, pp. 1727–1740. Philadelphia, PA: Wolters Kluwer; Lippincott Williams & Wilkins.
    Yamada S, Hatta M, Staker BL et al. (2010) Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathogens 6: e1001034.
    Zhu W, Higgs BW, Morehouse C et al. (2010) A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children. Vaccine 28: 2865–2876.
 Further Reading
    Das K, Aramini JM, Ma LC et al. (2010) Structures of influenza A proteins and insights into antiviral drug targets. Nature Structural Molecular Biology 17: 530–538.
    Neumann G, Noda T and Kawaoka Y (2009) Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459: 931–999.
    Rossman JS and Lamb RA (2009) Autophagy, apoptosis, and the influenza virus M2 protein. Cell Host & Microbe 6: 299–300.
    Schmolke M and Garcia-Sastre A (2010) Evasion of innate and adaptive immune responses by influenza A virus. Cell Microbiology 12: 873–880.
    Watanabe T, Watanabe S and Kawaoka Y (2010) Cellular networks involved in the influenza virus life cycle. Cell Host & Microbe 7: 427–439.

Related Sub-Topics:

Viruses Infecting Humans | RNA Viruses
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Influenza Viruses: Molecular Virology
 
How to Cite close
Neumann, Gabriele, and Kawaoka, Yoshihiro(Apr 2011) Influenza Viruses: Molecular Virology. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001031.pub3]