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The Influenza Virus: Structure and Replication

Figure 5 Model of influenza virus.

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  • 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.
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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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  • This figure was produced as described in the caption to Figure 6.
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  • 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.
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  • 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.
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  • 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.
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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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  • 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.
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Figure 8 Life cycle of influenza virus. (1) Binding of the virus to a sialic acid-containing receptor. (2) Engulfment of the virus by the cell plasma membrane and formation of an endocytic vesicle. (3) Delivery of the virus to the endosomal cell compartment. (4) Fusion of the viral membrane with the membrane of the endosome, induced by the mildly acidic pH in the endosomal lumen. (5) Delivery of viral RNA to the nucleus, synthesis of messenger RNA (mRNA) and viral RNA replication. (6) Synthesis of viral protein components in the cell cytosol (internal proteins) and endoplasmic reticulum (ER) (membrane proteins). (7) Assembly and budding of progeny viruses. source: Adapted with kind permission of Linda Stannard.

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  • The influenza virus genome, however, escapes degradation; through fusion of the viral envelope with the endosomal membrane, it gains access to the cell cytosol (Figure 8).
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  • The influenza virus genome, however, escapes degradation; through fusion of the viral envelope with the endosomal membrane, it gains access to the cell cytosol (Figure 8).
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  • This triggers the merging of the two membranes, involving the formation of a distinct hemifusion intermediate and the subsequent formation of a fusion pore (Figure 10) through which the viral genetic material gains direct access to the cytosol of the cell (Figure 8).
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  • The RNP complexes released into the host cell cytosol are transported to the nucleus (Figure 8).
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  • Synthesis of the viral envelope proteins HA, NA and M2 starts in the cytosol, but already during synthesis, the growing polypeptide chains are transported to the endoplasmic reticulum where the proteins are glycosylated and folded into trimers and tetramers (Figure 8).33,34 Subsequently, the proteins are transported through the Golgi apparatus and the trans-Golgi network to the plasma membrane of the cell.
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  • Subsequently, newly formed RNPs interact actively with the M1 lining at these patches (Figure 8).
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  • After attachment of RNPs to M1 on the inner half of the cell plasma membranes, in an intriguing process of budding, new virus particles are assembled (Figure 8).
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Figure 9 Conformational changes in the viral HA occurring at the pH of membrane fusion. The figure shows an HA monomer at neutral pH (left) and the low-pH form of HA2 both as a monomer and as a trimer (right). The long helices are represented in equivalent positions. As a result of the acid-induced conformational change in the molecule, the HA2 fusion peptides move upwards by about 10 nm to the tip of the trimer, such that they may insert into the endosomal membrane. Then the protein folds and induces membrane fusion, the fusion peptide and the C-terminal membrane anchor ultimately ending up in the same fused membrane. 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. source: Bullough PA et al. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 1994; 371: 37–43. 29 x PA Bullough, FM Hughson, JJ Skehel, DC Wiley. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371 (1994) (37 - 43) Crossref.

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  • This conformational change results in movement of the fusion peptide sequences of HA2, previously buried within the stem of the HA trimer, to the distal tip of the HA spike, allowing their insertion into the target membrane (Figure 9).28,29 Subsequently, a complex process of bending of the trimer takes place promoted by the formation of a stable coiled coil structure consisting of heptad repeat regions close to the fusion peptide and the transmembrane anchor of HA2.30 Thus, the two ends of HA2 inserted into the apposed membranes are brought together.
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Figure 10 Hypothetical mechanism of HA-mediated fusion between the influenza virus membrane and the endosomal membrane, involving the formation of a hemifusion diaphragm. The key step in the fusion process is the relocation of the fusion peptides of HA2 to the tip of the HA trimer such that they can penetrate the endosomal membrane (b); this step is triggered by the low pH in the endosome. source: Adapted from Cross KJ et al. Mechanisms of cell entry by influenza virus. Exp Rev Molec Med, 2001, Vol 6. ( www-ermm.cbcu.cam.ac.uk/01003453h.htm ) with permission from Cambridge University Press.

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  • This triggers the merging of the two membranes, involving the formation of a distinct hemifusion intermediate and the subsequent formation of a fusion pore (Figure 10) through which the viral genetic material gains direct access to the cytosol of the cell (Figure 8).
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Table 1 Natural hosts of influenza A viruses. The table indicates the subtypes of haemagglutinin (HA) and neuraminidase (NA), and the hosts in which they have been identified. 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.

Natural hosts of influenza A viruses
Haemagglutinin Neuraminidase
Subtype Predominant hosts Subtype Predominant hosts
H1 Human, pig, birds N1 Human, pig, birds
H2 Human, pig, birds N2 Human, pig, birds
H3 Birds, human, pig, horse N3 Birds
H4 Birds N4 Birds
H5 Birds, (human) N5 Birds
H6 Birds N6 Birds
H7 Birds, horse, (human) N7 Horse, birds
H8 Birds N8 Horse, birds
H9 Birds, (human) N9 Birds
H10 Birds
H11 Birds
H12 Birds
H13 Birds
H14 Birds
H15 Birds
H16 Birds

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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.
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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.
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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

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  • 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.
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