Influenza Viruses: Molecular Virology

Abstract

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 virusNS1 and NS2 mRNAs and their coding regions. NS1 and NS2 share 10 N‐terminal residues, including the initiating methionine. The reading frame of NS2mRNA (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 virusPB1 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 virusRNA 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 virusRNA 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.

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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.

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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]