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The Influenza Virus: Structure and Replication

Influenza virus structure

Influenza viruses are roughly spherical, although somewhat pleomorphic, particles, ranging from 80 to 120 nm in diameter. 1, x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) 7 x RWH Ruigrok. Structure of influenza A, B and C viruses. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (29 - 42) Figure 5 presents a model of the overall structure of the influenza virus. A characteristic feature of influenza virus particles is their external layer of approximately 500 spike-like projections. These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped). 7 x RWH Ruigrok. Structure of influenza A, B and C viruses. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (29 - 42) The HA spike is a trimer, consisting of three individual HA monomers, 8 x DA Steinhauer, SA Wharton. Structure and function of the haemagglutinin. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (54 - 64) while the NA spike is a tetramer. 9, x PM Colman. Structure and function of the neuraminidase. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (65 - 73) 10 x JN Varghese, WG Laver, PM Colman. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 Å resolution. Nature 303 (1983) (35 - 40) Crossref. HA is about four times more abundant than NA.

Figure 5 Model of influenza virus.

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References in context

  • Influenza viruses are roughly spherical, although somewhat pleomorphic, particles, ranging from 80 to 120 nm in diameter.1,7 Figure 5 presents a model of the overall structure of the influenza virus.
    Go to context

The viral envelope proteins

The major envelope glycoprotein HA is synthesized in the infected cell as a single polypeptide chain (HA0) with a length of approximately 560 amino acid residues, which is subsequently cleaved into two subunits, HA1 and HA2. 1, x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) 8 x DA Steinhauer, SA Wharton. Structure and function of the haemagglutinin. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (54 - 64) These subunits remain covalently linked to one another through disulphide bonds. Cleavage of HA0 is essential for the molecule to be able to mediate membrane fusion between the viral envelope and the host cell membrane, as discussed in more detail below. HA belongs to the first proteins for which the entire three-dimensional structure has been elucidated. Treatment of whole virions with the enzyme bromelain, which clips the polypeptide chain just above the viral membrane, releases a water-soluble fragment of the HA spike, commonly referred to as BHA. The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis. 8, x DA Steinhauer, SA Wharton. Structure and function of the haemagglutinin. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (54 - 64) 11 x IA Wilson, JJ Skehel, DC Wiley. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Nature 289 (1981) (366 - 373) Crossref. Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.

Figure 6 The three-dimensional structure of the influenza haemagglutinin (HA). The HA monomer (left) and trimer (right) are shown. In the monomer, the globular HA1 subunit is shown in dark blue, the HA2 subunit in light blue, with the “fusion peptide” in red. The receptor-binding site of HA1 is located at the tip of the molecule. This figure was produced by André van Eerde (University of Groningen), using MOLSCRIPT, on the basis of the co-ordinate file from the Protein Data Bank, code 3HMG. source: Weis WI et al. Refinement of the influenza virus hemagglutinin by simulated annealing. J Molec Biol 1990; 212: 737–761.

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References in context

  • This figure was produced as described in the caption to Figure 6.
    Go to context

  • This figure was produced using MOLSCRIPT, as described in the caption to Figure 6, on the basis of co-ordinate files from the Protein Data Bank, codes 3HMG and 1HTM.
    Go to context

  • The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis.8,11 Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.
    Go to context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

The HA spike protrudes approximately 13.5 nm from the viral surface. 11, x IA Wilson, JJ Skehel, DC Wiley. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Nature 289 (1981) (366 - 373) Crossref. 12 x JJ Skehel, DC Wiley. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69 (2000) (531 - 569) Crossref. HA1 and HA2 appear in the structure of the spike as distinct subunits. HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule ( Figure 6 ). 12 x JJ Skehel, DC Wiley. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69 (2000) (531 - 569) Crossref. HA1 also contains the major antigenic epitopes of the molecule ( Figure 7 ). 13 x DC Wiley, IA Wilson, JJ Skehel. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289 (1981) (373 - 378) Crossref. As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.

Figure 7 The location of the five major antigenic epitopes, A–E, on the HA1 subunit of the influenza virus haemagglutinin. 13 x DC Wiley, IA Wilson, JJ Skehel. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289 (1981) (373 - 378) Crossref. In the intact HA trimer, epitope D is not exposed and thus may not be involved in antibody induction. This figure was produced as described in the caption to Figure 6 .

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References in context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

HA2 forms the fibrous stem of the viral spike. The N-terminus of HA2 contains a conserved stretch of 20, mostly hydrophobic, amino acid residues. This sequence is generally referred to as the “fusion peptide”; it triggers the membrane fusion process between the viral envelope and the host cell membrane, 11, x IA Wilson, JJ Skehel, DC Wiley. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Nature 289 (1981) (366 - 373) Crossref. 12 x JJ Skehel, DC Wiley. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69 (2000) (531 - 569) Crossref. as discussed in more detail below.

The second envelope glycoprotein NA has enzymatic activity, cleaving sialic acid residues from glycoproteins or glycolipids. 9 x PM Colman. Structure and function of the neuraminidase. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (65 - 73) Since sialic acid functions as a receptor for attachment of influenza virions, the neuraminidase activity of NA, cleaving such receptors, 14 x GK Hirst. Adsorption of influenza haemagglutinins and virus by red blood cells. J Exp Med 76 (1942) (195 - 209) Crossref. mediates the release of newly formed virus particles from the surface of infected cells. 15 x P Palese, RW Compans. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol 33 (1976) (159 - 163) Crossref. NA is the target for the antiviral drugs oseltamivir (Tamiflu®) and zanamivir (Relenza®) (see Chapter 7). These drugs are sialic acid analogues, 16 x M Von Itzstein, WY Wu, GB Kok, et al.. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363 (1993) (418 - 423) Crossref. which inhibit the enzymatic activity of NA, thus slowing down the release of progeny virus from infected cells.

The influenza A virus envelope contains a small number of copies of a third integral membrane protein, M2, which forms a tetramer with ion channel activity.17, 18, and 19 x AJ Hay. Functional properties of the virus ion channels. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (74 - 81) x RA Lamb, SL Zebedee, CD Richardson. Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface. Cell 40 (1985) (627 - 633) Crossref. x SL Zebedee, RA Lamb. Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions. J Virol 62 (1988) (2762 - 2772) M2 is involved in the infection process by modulating the pH within virions, weakening the interaction between the viral ribonucleoproteins (RNPs) and the M1 protein. M2 is the target for the anti-influenza drugs amantadine and rimantadine. 20 x AJ Hay. The action of adamantanamines against influenza A viruses: inhibition of the M2 channel protein. Semin Virol 3 (1992) (21 - 30) Influenza B viruses also contain a similarly limited number of copies of the integral membrane protein NB. 17 x AJ Hay. Functional properties of the virus ion channels. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (74 - 81) This protein may well be a functional homologue of the M2 protein of the A viruses, but it is not inhibited by amantadine and rimantadine. Thus, these antiviral drugs are not effective against influenza B (see also Chapter 7).

The viral core

The influenza A or B virus genome consists of eight segments of negative-sense single-stranded RNA. 1 x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) Each RNA segment is associated with multiple copies of NP and with the viral transcriptase consisting of RNA polymerase components PB1, PB2 and PA, thus forming the RNP complex. 21 x T Noda, H Sagara, A Yen, et al.. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature 439 (2006) (490 - 492) Crossref. The RNPs are surrounded by a layer of the matrix protein, M1. With approximately 3000 copies per virion, M1 is the most abundant structural protein of influenza virus. 1 x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531)

RNA segments 1–6 of influenza A viruses encode a single protein each. 1 x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) For example, segment 4 encodes the HA, segment 5 NP and segment 6 the NA protein. Segment 7 encodes two proteins, M1 and M2, with overlapping reading frames. Likewise, segment 8 encodes the non-structural proteins NS1 and NS2, again with superimposed reading frames. Even though NS2 was originally thought to be absent from virus particles (hence the name “non-structural”), it has subsequently been found in low copy numbers in virions. NS1 is not present in virions, but it is abundant in infected cells. Table 2 presents a survey of the RNA segments and the corresponding gene products of influenza A viruses.

Table 2 Influenza A virus RNA segments and the proteins they encode. Influenza A viruses have eight gene segments encoding 10 different proteins, segments 7 and 8 encoding two proteins each. source: Adapted from Lamb RA, Krug RM. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Howley PM, Griffin DE et al., editors. Fields Virology, 4th edn. Lippincott Williams & Wilkins, 2001; pp. 1487–1531 1 x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) with permission from Lippincott Williams & Wilkins.

Influenza A virus RNA segments and the proteins they encode
RNA segment (no. of nucleotides) Gene product (no. of amino acids) Molecules per virion
1 (2341) Polymerase PB2 (759) 30–60
2 (2341) Polymerase PB1 (757) 30–60
3 (2233) Polymerase PA (716) 30–60
4 (1778) Haemagglutinin (566) 500
5 (1565) Nucleoprotein (498) 1000
6 (1413) Neuraminidase (454) 100
7 (1027) Matrix protein M1 (252) 3000
Matrix protein M2 (97) 20–60
8 (890) Non-structural proteins
  • NS1 (230)
  • NS2 (121)
130–200

References in context

  • NS1 is not present in virions, but it is abundant in infected cells. Table 2 presents a survey of the RNA segments and the corresponding gene products of influenza A viruses.
    Go to context

 
x

Figure 5 Model of influenza virus.

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References in context

  • Influenza viruses are roughly spherical, although somewhat pleomorphic, particles, ranging from 80 to 120 nm in diameter.1,7 Figure 5 presents a model of the overall structure of the influenza virus.
    Go to context

Figure 6 The three-dimensional structure of the influenza haemagglutinin (HA). The HA monomer (left) and trimer (right) are shown. In the monomer, the globular HA1 subunit is shown in dark blue, the HA2 subunit in light blue, with the “fusion peptide” in red. The receptor-binding site of HA1 is located at the tip of the molecule. This figure was produced by André van Eerde (University of Groningen), using MOLSCRIPT, on the basis of the co-ordinate file from the Protein Data Bank, code 3HMG. source: Weis WI et al. Refinement of the influenza virus hemagglutinin by simulated annealing. J Molec Biol 1990; 212: 737–761.

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References in context

  • This figure was produced as described in the caption to Figure 6.
    Go to context

  • This figure was produced using MOLSCRIPT, as described in the caption to Figure 6, on the basis of co-ordinate files from the Protein Data Bank, codes 3HMG and 1HTM.
    Go to context

  • The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis.8,11 Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.
    Go to context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

Figure 7 The location of the five major antigenic epitopes, A–E, on the HA1 subunit of the influenza virus haemagglutinin. 13 x DC Wiley, IA Wilson, JJ Skehel. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289 (1981) (373 - 378) Crossref. In the intact HA trimer, epitope D is not exposed and thus may not be involved in antibody induction. This figure was produced as described in the caption to Figure 6 .

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References in context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

Table 2 Influenza A virus RNA segments and the proteins they encode. Influenza A viruses have eight gene segments encoding 10 different proteins, segments 7 and 8 encoding two proteins each. source: Adapted from Lamb RA, Krug RM. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Howley PM, Griffin DE et al., editors. Fields Virology, 4th edn. Lippincott Williams & Wilkins, 2001; pp. 1487–1531 1 x RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) with permission from Lippincott Williams & Wilkins.

Influenza A virus RNA segments and the proteins they encode
RNA segment (no. of nucleotides) Gene product (no. of amino acids) Molecules per virion
1 (2341) Polymerase PB2 (759) 30–60
2 (2341) Polymerase PB1 (757) 30–60
3 (2233) Polymerase PA (716) 30–60
4 (1778) Haemagglutinin (566) 500
5 (1565) Nucleoprotein (498) 1000
6 (1413) Neuraminidase (454) 100
7 (1027) Matrix protein M1 (252) 3000
Matrix protein M2 (97) 20–60
8 (890) Non-structural proteins
  • NS1 (230)
  • NS2 (121)
130–200

References in context

  • NS1 is not present in virions, but it is abundant in infected cells. Table 2 presents a survey of the RNA segments and the corresponding gene products of influenza A viruses.
    Go to context

References

Label Authors Title Source Year
1

References in context


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  • Influenza A, B and C viruses also differ with respect to host range, variability of the surface glycoproteins, genome organization and morphology.1 The influenza A viruses are responsible for pandemic outbreaks of influenza and for most of the well-known annual flu epidemics.2 Therefore, the discussion here will be limited primarily to influenza A viruses, only referring to influenza B where appropriate.
    Go to context

  • Influenza A, B and C viruses also differ with respect to host range, variability of the surface glycoproteins, genome organization and morphology.1 The influenza A viruses are responsible for pandemic outbreaks of influenza and for most of the well-known annual flu epidemics.2 Therefore, the discussion here will be limited primarily to influenza A viruses, only referring to influenza B where appropriate.
    Go to context

  • The A and B viruses contain two major envelope glycoproteins, haemagglutinin (HA) and neuraminidase (NA).1 An important feature of influenza viruses is their segmented genome, containing eight independent RNA strands of negative polarity.
    Go to context

  • The A and B viruses contain two major envelope glycoproteins, haemagglutinin (HA) and neuraminidase (NA).1 An important feature of influenza viruses is their segmented genome, containing eight independent RNA strands of negative polarity.
    Go to context

  • Human-to-human transmission of influenza occurs through aerosols or droplets, spread into the environment by a sneezing or coughing infected individual.3 The virus attacks primarily epithelial cells of the upper and lower respiratory tract.2 Infection occurs by binding of the viral HA to sialic acid receptors on the target cell surface and subsequent fusion of the viral envelope with the host cell membrane.1 It is through this fusion process that the viral RNA gains access to the cytosol of the host cell.
    Go to context

  • Human-to-human transmission of influenza occurs through aerosols or droplets, spread into the environment by a sneezing or coughing infected individual.3 The virus attacks primarily epithelial cells of the upper and lower respiratory tract.2 Infection occurs by binding of the viral HA to sialic acid receptors on the target cell surface and subsequent fusion of the viral envelope with the host cell membrane.1 It is through this fusion process that the viral RNA gains access to the cytosol of the host cell.
    Go to context

  • Influenza A viruses are known to also infect a variety of other mammals, including non-human primates, pigs, horses, cats, seals, whales and mink (Table 1).1,2,4 There are no influenza B virus subtypes.
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  • Influenza A viruses are known to also infect a variety of other mammals, including non-human primates, pigs, horses, cats, seals, whales and mink (Table 1).1,2,4 There are no influenza B virus subtypes.
    Go to context

  • Influenza viruses are roughly spherical, although somewhat pleomorphic, particles, ranging from 80 to 120 nm in diameter.1,7 Figure 5 presents a model of the overall structure of the influenza virus.
    Go to context

  • The major envelope glycoprotein HA is synthesized in the infected cell as a single polypeptide chain (HA0) with a length of approximately 560 amino acid residues, which is subsequently cleaved into two subunits, HA1 and HA2.1,8 These subunits remain covalently linked to one another through disulphide bonds.
    Go to context

  • The influenza A or B virus genome consists of eight segments of negative-sense single-stranded RNA.1 Each RNA segment is associated with multiple copies of NP and with the viral transcriptase consisting of RNA polymerase components PB1, PB2 and PA, thus forming the RNP complex.21 The RNPs are surrounded by a layer of the matrix protein, M1.
    Go to context

  • The influenza A or B virus genome consists of eight segments of negative-sense single-stranded RNA.1 Each RNA segment is associated with multiple copies of NP and with the viral transcriptase consisting of RNA polymerase components PB1, PB2 and PA, thus forming the RNP complex.21 The RNPs are surrounded by a layer of the matrix protein, M1.
    Go to context

  • RNA segments 1–6 of influenza A viruses encode a single protein each.1 For example, segment 4 encodes the HA, segment 5 NP and segment 6 the NA protein.
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  • Here, the negative-sense viral RNAs are transcribed to positive-sense messenger RNAs (mRNAs) by the transcriptase (consisting of PB1, PB2 and PA) carried with the RNPs.1 The transcriptase, in a process referred to as “cap snatching”, steals short cap regions from cellular mRNAs as primers for initiation of viral mRNA synthesis.
    Go to context

  • Thus, cleavage of HA0 is essential for viral infectivity.1,11,12,28,29 In human influenza viruses, cleavage is thought to occur extracellularly, at a single arginine residue, after HA0 has been incorporated in virus particles.37 The enzyme responsible for cleavage, a trypsin-like protease, is probably released from Clara cells in the respiratory epithelium.
    Go to context

RA Lamb, RM Krug. Orthomyxoviridae: the viruses and their replication. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1487 - 1531) 2001
7

References in context

  • These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped).7 The HA spike is a trimer, consisting of three individual HA monomers,8 while the NA spike is a tetramer.9,10 HA is about four times more abundant than NA.
    Go to context

  • These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped).7 The HA spike is a trimer, consisting of three individual HA monomers,8 while the NA spike is a tetramer.9,10 HA is about four times more abundant than NA.
    Go to context

RWH Ruigrok. Structure of influenza A, B and C viruses. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (29 - 42) 1998
8

References in context

  • These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped).7 The HA spike is a trimer, consisting of three individual HA monomers,8 while the NA spike is a tetramer.9,10 HA is about four times more abundant than NA.
    Go to context

  • The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis.8,11 Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.
    Go to context

  • The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis.8,11 Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.
    Go to context

DA Steinhauer, SA Wharton. Structure and function of the haemagglutinin. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (54 - 64) 1998
9

References in context

  • These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped).7 The HA spike is a trimer, consisting of three individual HA monomers,8 while the NA spike is a tetramer.9,10 HA is about four times more abundant than NA.
    Go to context

  • The second envelope glycoprotein NA has enzymatic activity, cleaving sialic acid residues from glycoproteins or glycolipids.9 Since sialic acid functions as a receptor for attachment of influenza virions, the neuraminidase activity of NA, cleaving such receptors,14 mediates the release of newly formed virus particles from the surface of infected cells.15 NA is the target for the antiviral drugs oseltamivir (Tamiflu®) and zanamivir (Relenza®) (see Chapter 7).
    Go to context

  • As indicated above, the viral HA binds to sialic acid residues on glycoproteins or glycolipids on the cell surface.9 The fine specificity of HA's receptor binding depends on the nature of the glycosidic linkage between the terminal sialic acid and the penultimate galactose residue on the receptor.22 Human influenza viruses preferentially bind to sialic acids attached to galactose in an α2,6 configuration, whereas avian viruses have a preference for sialic acids attached to galactose in an α2,3 linkage.23 This difference is thought to be the basis for the very inefficient transmission of avian influenza viruses to humans.
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PM Colman. Structure and function of the neuraminidase. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (65 - 73) 1998
10

References in context

  • These spikes represent the envelope glycoproteins HA (which has a rod-like shape) and NA (which is mushroom-shaped).7 The HA spike is a trimer, consisting of three individual HA monomers,8 while the NA spike is a tetramer.9,10 HA is about four times more abundant than NA.
    Go to context

JN Varghese, WG Laver, PM Colman. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 Å resolution. Crossref. Nature 303 (1983) (35 - 40) 1983
11

References in context

  • The ectodomain of HA of A/Aichi/2/68 (H3N2) virus, related to the Hong Kong pandemic virus of 1968, has thus been crystallized and subjected to X-ray analysis.8,11 Figure 6 presents a representation of the 3D structure of HA based on this pioneering X-ray crystallographic structure determination.
    Go to context

  • The HA spike protrudes approximately 13.5 nm from the viral surface.11,12 HA1 and HA2 appear in the structure of the spike as distinct subunits.
    Go to context

  • This sequence is generally referred to as the “fusion peptide”; it triggers the membrane fusion process between the viral envelope and the host cell membrane,11,12 as discussed in more detail below.
    Go to context

  • Thus, cleavage of HA0 is essential for viral infectivity.1,11,12,28,29 In human influenza viruses, cleavage is thought to occur extracellularly, at a single arginine residue, after HA0 has been incorporated in virus particles.37 The enzyme responsible for cleavage, a trypsin-like protease, is probably released from Clara cells in the respiratory epithelium.
    Go to context

IA Wilson, JJ Skehel, DC Wiley. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Crossref. Nature 289 (1981) (366 - 373) 1981
12

References in context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

  • This sequence is generally referred to as the “fusion peptide”; it triggers the membrane fusion process between the viral envelope and the host cell membrane,11,12 as discussed in more detail below.
    Go to context

  • Thus, cleavage of HA0 is essential for viral infectivity.1,11,12,28,29 In human influenza viruses, cleavage is thought to occur extracellularly, at a single arginine residue, after HA0 has been incorporated in virus particles.37 The enzyme responsible for cleavage, a trypsin-like protease, is probably released from Clara cells in the respiratory epithelium.
    Go to context

JJ Skehel, DC Wiley. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Crossref. Annu Rev Biochem 69 (2000) (531 - 569) 2000
13

References in context

  • The location of the five major antigenic epitopes, A–E, on the HA1 subunit of the influenza virus haemagglutinin.13 In the intact HA trimer, epitope D is not exposed and thus may not be involved in antibody induction.
    Go to context

  • HA1, the globular domain at the distal end of the spike, is responsible for binding of the virus to its cellular sialic acid receptor, the receptor-binding pocket being located close to the very tip of the molecule (Figure 6).12 HA1 also contains the major antigenic epitopes of the molecule (Figure 7).13 As discussed in more detail in Chapter 4, HA is the primary viral antigen to which the host's antibody response is directed and the only antigen inducing a virus-neutralizing response.
    Go to context

DC Wiley, IA Wilson, JJ Skehel. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Crossref. Nature 289 (1981) (373 - 378) 1981
14

References in context

  • The second envelope glycoprotein NA has enzymatic activity, cleaving sialic acid residues from glycoproteins or glycolipids.9 Since sialic acid functions as a receptor for attachment of influenza virions, the neuraminidase activity of NA, cleaving such receptors,14 mediates the release of newly formed virus particles from the surface of infected cells.15 NA is the target for the antiviral drugs oseltamivir (Tamiflu®) and zanamivir (Relenza®) (see Chapter 7).
    Go to context

GK Hirst. Adsorption of influenza haemagglutinins and virus by red blood cells. Crossref. J Exp Med 76 (1942) (195 - 209) 1942
15

References in context

  • The second envelope glycoprotein NA has enzymatic activity, cleaving sialic acid residues from glycoproteins or glycolipids.9 Since sialic acid functions as a receptor for attachment of influenza virions, the neuraminidase activity of NA, cleaving such receptors,14 mediates the release of newly formed virus particles from the surface of infected cells.15 NA is the target for the antiviral drugs oseltamivir (Tamiflu®) and zanamivir (Relenza®) (see Chapter 7).
    Go to context

  • It is at this point that the viral NA cleaves the sialic acid, thus releasing the virions from the host cell's surface,15 allowing them to spread further throughout the respiratory tract.
    Go to context

P Palese, RW Compans. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. Crossref. J Gen Virol 33 (1976) (159 - 163) 1976
16

References in context

  • These drugs are sialic acid analogues,16 which inhibit the enzymatic activity of NA, thus slowing down the release of progeny virus from infected cells.
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M Von Itzstein, WY Wu, GB Kok, et al.. Rational design of potent sialidase-based inhibitors of influenza virus replication. Crossref. Nature 363 (1993) (418 - 423) 1993
17

References in context

  • The influenza A virus envelope contains a small number of copies of a third integral membrane protein, M2, which forms a tetramer with ion channel activity.17–19 M2 is involved in the infection process by modulating the pH within virions, weakening the interaction between the viral ribonucleoproteins (RNPs) and the M1 protein.
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  • M2 is the target for the anti-influenza drugs amantadine and rimantadine.20 Influenza B viruses also contain a similarly limited number of copies of the integral membrane protein NB.17 This protein may well be a functional homologue of the M2 protein of the A viruses, but it is not inhibited by amantadine and rimantadine.
    Go to context

  • This acidification is mediated by the M2 proton channel in the viral envelope mentioned above.17,20,31 After exposure of the virus to pH 5–6 within the lumen of the endosome, protons flow into the viral interior, weakening interaction of the M1 protein layer with the viral envelope and the RNPs.
    Go to context

  • This acidification is mediated by the M2 proton channel in the viral envelope mentioned above.17,20,31 After exposure of the virus to pH 5–6 within the lumen of the endosome, protons flow into the viral interior, weakening interaction of the M1 protein layer with the viral envelope and the RNPs.
    Go to context

  • As it happens, the M2 protein, which is abundantly expressed in infected cells, transiently neutralizes the pH within the trans-Golgi network, such that HA may transit safely to the cell surface.17,20 This represents a second important function of the M2 protein, besides its role in viral entry and uncoating discussed above.
    Go to context

AJ Hay. Functional properties of the virus ion channels. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (74 - 81) 1998
18

References in context

  • The influenza A virus envelope contains a small number of copies of a third integral membrane protein, M2, which forms a tetramer with ion channel activity.17–19 M2 is involved in the infection process by modulating the pH within virions, weakening the interaction between the viral ribonucleoproteins (RNPs) and the M1 protein.
    Go to context

RA Lamb, SL Zebedee, CD Richardson. Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface. Crossref. Cell 40 (1985) (627 - 633) 1985
19

References in context

  • The influenza A virus envelope contains a small number of copies of a third integral membrane protein, M2, which forms a tetramer with ion channel activity.17–19 M2 is involved in the infection process by modulating the pH within virions, weakening the interaction between the viral ribonucleoproteins (RNPs) and the M1 protein.
    Go to context

SL Zebedee, RA Lamb. Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions. J Virol 62 (1988) (2762 - 2772) 1988
20

References in context

  • M2 is the target for the anti-influenza drugs amantadine and rimantadine.20 Influenza B viruses also contain a similarly limited number of copies of the integral membrane protein NB.17 This protein may well be a functional homologue of the M2 protein of the A viruses, but it is not inhibited by amantadine and rimantadine.
    Go to context

  • This acidification is mediated by the M2 proton channel in the viral envelope mentioned above.17,20,31 After exposure of the virus to pH 5–6 within the lumen of the endosome, protons flow into the viral interior, weakening interaction of the M1 protein layer with the viral envelope and the RNPs.
    Go to context

  • This acidification is mediated by the M2 proton channel in the viral envelope mentioned above.17,20,31 After exposure of the virus to pH 5–6 within the lumen of the endosome, protons flow into the viral interior, weakening interaction of the M1 protein layer with the viral envelope and the RNPs.
    Go to context

  • As it happens, the M2 protein, which is abundantly expressed in infected cells, transiently neutralizes the pH within the trans-Golgi network, such that HA may transit safely to the cell surface.17,20 This represents a second important function of the M2 protein, besides its role in viral entry and uncoating discussed above.
    Go to context

AJ Hay. The action of adamantanamines against influenza A viruses: inhibition of the M2 channel protein. Semin Virol 3 (1992) (21 - 30) 1992
21

References in context

  • The influenza A or B virus genome consists of eight segments of negative-sense single-stranded RNA.1 Each RNA segment is associated with multiple copies of NP and with the viral transcriptase consisting of RNA polymerase components PB1, PB2 and PA, thus forming the RNP complex.21 The RNPs are surrounded by a layer of the matrix protein, M1.
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  • It has long been thought that the packaging of RNPs into new virions occurs in a random fashion.
    Go to context

T Noda, H Sagara, A Yen, et al.. Architecture of ribonucleoprotein complexes in influenza A virus particles. Crossref. Nature 439 (2006) (490 - 492) 2006

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