Elsevier Health Sciences

Topics

« Back to Resource Center

The Influenza Virus: Structure and Replication

References

Label Authors Title Source Year
1

References in context


  • Go to context


  • 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

  • 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.
    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.
    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.
    Go to context

  • 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
2

References in 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

  • 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.
    Go to context

PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) 2001
3

References in 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

MR Moser, TR Bender, HS Margolis, et al.. An outbreak of influenza aboard a commercial airliner. Am J Epidemiol 110 (1979) (1 - 6) 1979
4

References in 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.
    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.
    Go to context

VS Hinshaw, RG Webster, WJ Bean, G Sriram. The ecology of influenza viruses in ducks and analysis of influenza viruses with monoclonal antibodies. Crossref. Comp Immunol Microbiol Infect Dis 3 (1980) (155 - 164) 1980
5

References in context

  • Influenza A viruses are divided into subtypes, based on the nature of their surface glycoproteins, HA and NA.1 There are 16 different HAs and nine NAs which are distinguishable serologically, i.e. antibodies to one virus subtype do not react with another.
    Go to context

ADME Osterhaus, GF Rimmelzwaan, BE Martina, TM Bestebroer, RAM Fouchier. Influenza B virus in seals. Crossref. Science 288 (2000) (1051 - 1053) 2000
6

References in context

  • The current nomenclature system for influenza A viruses includes the host of origin, geographic location of first isolation, strain number and year of isolation.6 The HA and NA subtype of influenza A viruses is specified in parentheses, e.g.
    Go to context

WHO Memorandum. A revised system for nomenclature of influenza viruses. Bull World Health Org 58 (1980) (585 - 591) 1980
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.
    Go to context

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.
    Go to context

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.
    Go to 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. 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.
    Go to context

  • 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
22

References in 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.
    Go to context

W Weis, JH Brown, S Cusack, et al.. Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Crossref. Nature 333 (1988) (426 - 431) 1988
23

References in context

  • Pigs, on the other hand, have receptors with either type of linkage between sialic acid and galactose, and thus are readily susceptible to infection with both human and avian viruses.23 Co-infection of pigs with different influenza viruses is considered one mechanism by which new influenza viruses with pandemic potential may arise (see also Chapter 3).
    Go to context

  • Pigs, on the other hand, have receptors with either type of linkage between sialic acid and galactose, and thus are readily susceptible to infection with both human and avian viruses.23 Co-infection of pigs with different influenza viruses is considered one mechanism by which new influenza viruses with pandemic potential may arise (see also Chapter 3).
    Go to context

T Ito, JN Couceiro, S Kelm, et al.. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 72 (1998) (7367 - 7373) 1998
24

References in context

  • The vesicles thus formed subsequently fuse with intracellular compartments called endosomes, as a result of which the virus is delivered to the endosomal lumen.24–26 Receptor-mediated endocytosis is not specific for uptake of viruses.
    Go to context

  • It is the low pH inside the endosomes (pH 5–6), maintained by proton pumps within the endosomal membrane, that triggers the fusion reaction between the viral envelope and the endosomal membrane.24–27 This is a key step in the viral infection mechanism.
    Go to context

KS Matlin, H Reggio, A Helenius, K Simons. Infectious entry pathway of influenza virus in a canine kidney cell line. Crossref. J Cell Biol 91 (1981) (601 - 613) 1981
25

References in context

  • The vesicles thus formed subsequently fuse with intracellular compartments called endosomes, as a result of which the virus is delivered to the endosomal lumen.24–26 Receptor-mediated endocytosis is not specific for uptake of viruses.
    Go to context

  • It is the low pH inside the endosomes (pH 5–6), maintained by proton pumps within the endosomal membrane, that triggers the fusion reaction between the viral envelope and the endosomal membrane.24–27 This is a key step in the viral infection mechanism.
    Go to context

MJ Rust, M Lakadamyali, F Zhang, et al.. Assembly of endocytic machinery around individual influenza viruses during viral entry. Crossref. Nat Struct Mol Biol 11 (2004) (567 - 573) 2004
26

References in context

  • The vesicles thus formed subsequently fuse with intracellular compartments called endosomes, as a result of which the virus is delivered to the endosomal lumen.24–26 Receptor-mediated endocytosis is not specific for uptake of viruses.
    Go to context

  • It is the low pH inside the endosomes (pH 5–6), maintained by proton pumps within the endosomal membrane, that triggers the fusion reaction between the viral envelope and the endosomal membrane.24–27 This is a key step in the viral infection mechanism.
    Go to context

AE Smith, A Helenius. How viruses enter animal cells. Crossref. Science 304 (2004) (237 - 242) 2004
27

References in context

  • It is the low pH inside the endosomes (pH 5–6), maintained by proton pumps within the endosomal membrane, that triggers the fusion reaction between the viral envelope and the endosomal membrane.24–27 This is a key step in the viral infection mechanism.
    Go to context

T Stegmann, HW Morselt, J Scholma, J Wilschut. Fusion of influenza virus in an intracellular acidic compartment measured by fluorescence dequenching. Crossref. Biochim Biophys Acta 904 (1987) (165 - 170) 1987
28

References in context

  • 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.
    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

CM Kim Carr, PS Kim. A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 73 (1993) (823 - 832) 1993
29

References in context


  • Go to context

  • 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.
    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

PA Bullough, FM Hughson, JJ Skehel, DC Wiley. Structure of influenza haemagglutinin at the pH of membrane fusion. Crossref. Nature 371 (1994) (37 - 43) 1994
30

References in context

  • 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.
    Go to context

J Chen, JJ Skehel, DC Wiley. N- and C-terminal residues combine in the fusion–pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil. Crossref. Proc Natl Acad Sci USA 96 (1999) (8967 - 8972) 1999
31

References in 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

A Helenius. Unpacking the incoming influenza virus. Crossref. Cell 69 (1992) (577 - 578) 1992
32

References in context

  • The release of the viral RNPs from the endosome into the cytoplasm is facilitated by acidification of the viral interior prior to the fusion step.
    Go to context

R Bron, AP Kendal, HD Klenk, J Wilschut. Role of the M2 protein in influenza virus membrane fusion: effects of amantadine and monensin on fusion kinetics. Crossref. Virology 195 (1993) (808 - 811) 1993
33

References in context

  • 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.
    Go to context

I Braakman, H Hoover-Litty, KR Wagner, A Helenius. Folding of influenza hemagglutinin in the endoplasmic reticulum. Crossref. J Cell Biol 114 (1991) (401 - 411) 1991
34

References in context

  • 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.
    Go to context

RW Doms, RA Lamb, JK Rose, A Helenius. Folding and assembly of viral membrane proteins. Crossref. Virology 193 (1993) (545 - 562) 1993
35

References in context

  • In polarized epithelial cells, this process occurs exclusively on the apical side of the cells, HA and NA being sorted to this (“exterior”) surface of the cells’ plasma membrane.35 As a result, progeny virus is released back to the airways and not to the systemic circulation.
    Go to context

E Rodriguez-Boulan, DD Sabatini. Asymmetric budding of viruses in epithelial monlayers: a model system for study of epithelial polarity. Proc Natl Acad Sci USA 75 (1978) (5071 - 5075) 1978
36

References in context

  • It has long been thought that the packaging of RNPs into new virions occurs in a random fashion.
    Go to context

Y Fujii, H Goto, T Watanabe, T Yoshida, Y Kawaoka. Selective incorporation of influenza virus RNA segments into virions. Crossref. Proc Natl Acad Sci USA 100 (2003) (2002 - 2007) 2003
37

References in 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

  • For avian influenza viruses, the situation is somewhat different and appears to be closely related to the pathogenicity of these viruses in birds.37,38 HAs of non-virulent or low-pathogenicity avian influenza (LPAI) viruses have a single basic cleavage site similar to that in HAs of human viruses, restricting the spread of these viruses.
    Go to context

  • It is not clear whether the presence of a multibasic cleavage site in HA0 also represents an important determinant of viral pathogenicity in humans.37 The HA of the extrememely pathogenic Spanish flu virus (see Chapter 3) does not have the multibasic cleavage site.39 On the other hand, infection of humans with the highly pathogenic H5N1 avian influenza virus, the HA of which does have the multibasic cleavage site, exhibits a very high case-fatality rate, with six deaths from 18 confirmed cases in Hong Kong in 1997 and 94 deaths among 179 confirmed infections thusfar (March 1, 2006) in Asia and Turkey during the more recent H5N1 outbreaks in these areas.
    Go to context

DA Steinhauer. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Crossref. Virology 258 (1999) (1 - 20) 1999
38

References in context

  • For avian influenza viruses, the situation is somewhat different and appears to be closely related to the pathogenicity of these viruses in birds.37,38 HAs of non-virulent or low-pathogenicity avian influenza (LPAI) viruses have a single basic cleavage site similar to that in HAs of human viruses, restricting the spread of these viruses.
    Go to context

H-D Klenk, W Garten. Host cell proteases controlling virus pathogenicity. Crossref. Trends Microbiol 2 (1994) (39 - 43) 1994
39

References in context

  • It is not clear whether the presence of a multibasic cleavage site in HA0 also represents an important determinant of viral pathogenicity in humans.37 The HA of the extrememely pathogenic Spanish flu virus (see Chapter 3) does not have the multibasic cleavage site.39 On the other hand, infection of humans with the highly pathogenic H5N1 avian influenza virus, the HA of which does have the multibasic cleavage site, exhibits a very high case-fatality rate, with six deaths from 18 confirmed cases in Hong Kong in 1997 and 94 deaths among 179 confirmed infections thusfar (March 1, 2006) in Asia and Turkey during the more recent H5N1 outbreaks in these areas.
    Go to context

AH Reid, TG Fanning, JV Hultin, JK Taubenberger. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Crossref. Proc Natl Acad Sci USA 96 (1999) (1651 - 1656) 1999

« Back to Resource Center