History and classification of the influenza virus

Influenza viruses are the cause of outbreaks of acute respiratory disease, known as influenza or ‘flu’, which has afflicted man and animals since ancient times. The name influenza has its origin in early fifteenth century Italy and was adopted in Europe to explain the sudden appearance of an epidemic disease thought to be under the influence of the stars. The viruses are classified as members of the family Orthomyxoviridae (from the Greek orthos, ’standard, correct’, and myxo, ‘mucus’) because of their ability to bind to mucus, and to distinguish them from a second family of enveloped negative-strand RNA viruses, the Paramyxoviridae (reviewed in [22]). The Orthomyxoviridae are divided into two genera: influenza A and B viruses, and influenza C virus. The three virus types can be distinguished from one another on the basis of antigenic differences between their nucleoproteins (NP) and matrix (M) proteins.13]. The type A viruses are further divided into subtypes, based on the antigenic nature of their surface glycoproteins haemagglutinin (HA) and neuraminidase (NA). So far, 15 different HAs (H1 to 15) and 9 NAs (N1 to 9) have been identified among all influenza viruses.33], and three years later a virus shown to be related to that from the pig was eventually isolated from a human patient. The virus was cultured by inoculating a filtrate of the patient’s throat washings into the noses of ferrets, which are highly susceptible to influenza virus [34]. The isolate was later classified as influenza A virus and was followed in 1940 and 1947 by the isolation and classification of influenza B and C viruses, respectively.

Influenza B and C viruses are almost exclusively isolated from man, although influenza C virus has also been isolated from pigs and influenza B has recently been isolated from seals. Influenza A viruses, in contrast, infect a wide range of avian and mammalian species, with the latter group including man, pigs, horses and aquatic mammals [

Despite influenza being an important disease of man, the virus was first isolated from poultry. A disease causing extremely high mortality in domestic fowl was first described in 1878 and became known as ‘fowl plague’. As early as 1901 the causative agent was shown to be an ultra-filterable agent (i.e. ‘virus’), although it was not until 1955 that the close relationship between this agent and mammalian influenza A viruses was demonstrated. Isolation of influenza virus from pigs also preceded that from man. The virus was the causative agent of a ‘new’ disease of pigs, termed ‘swine influenza’. It gave clinical signs similar to those observed in man, which were described for the first time during the 1918 human pandemic. In 1930, Shope demonstrated that swine influenza virus could be transmitted between pigs using ultrafiltered material [

The current system of nomenclature of influenza viruses was introduced in 1980 and designates the type, host, place, strain number (if any), year of isolation and antigenic subtype of a virus. For example, a swine influenza virus isolated in Wisconsin in 1984 would be designated A/Swine/Wisconsin/1/84(H1N1).



Figure 1. Electron micrographs of purified influenza virions (A and B, magnification: x 159,250) and virions budding from the surface of Madin-Darby canine kidney (MDCK) cells (C and D, magnification: x 40,600). The influenza virus has been stained with 10 nm gold labelled antibodies to (A) the surface glycoprotein haemagglutinin (HA) and (B) the transmembrane protein matrix protein 2 (M2). Courtesy of George Leser, Northwestern University, Evanston, IL.The virus
An enormous amount of information is available the antigenic, genetic, structural and biological characteristics of influenza A viruses (for review, see [22, 27]). They have a spherical or filamentous morphology and are medium-sized, with a diameter of 80 to 120 nm (Figure 1). The virus is enveloped, and the lipid membrane of the virion is derived from the host cell in which the virus replicated. From the surface of the envelope extend the two transmembrane glycoproteins HA and NA, which are commonly called ’spikes’ (Figure 2). A third transmembrane protein, matrix protein M2, also exists but only 20-60 molecules per virion are present. The matrix protein M1 forms a layer beneath the envelope and so gives structure to the virus and encapsidates the ribonucleoprotein (RNP) complexes. RNP complexes consist of ribonucleic acid (RNA) associated with nucleoprotein (NP) as well as the polymerases PA, PB1 and PB2 that are responsible for RNA replication and transcription. Two non-structural proteins are also associated with the virus: NS2 is found in the virion while NS1 is found only in infected cells. The influenza virus genome consists of eight unique segments of single-stranded RNA which have negative polarity. Each RNA strand encodes only one protein, except for strands 7 and 8 which encode two (Table 1).




Figure 2. Schematic representation of influenza A virus.
(Reproduced with permission from Fields Virology. Third edition. Lippincott Williams and Wilkins, Philadelphia [



Table 1. Influenza A virus gene segments and encoded proteins (adapted from Lamb and Krug, 1996 [22])The replication cycle of influenza virus starts with the cleavage of HA into HA1 and HA2 by enzymes present in the respiratory tract. The enzymes are produced by the host but may also be derived from bacteria, which, therefore, can promote the influenza infection. Virus grown in cells that lack a cleavage enzyme can be activated by treatment with trypsin. After HA cleavage, the receptor-binding site of HA1 can attach to a terminal sialic acid residue of a cell surface receptor; once attached to the host cell the virus is endocytosed (receptor-mediated endocytosis) (Figure 3). NA functions as a receptor-destroying enzyme by cleaving terminal sialic acid residues from the receptor. Thus, NA releases progeny virions from the host cell in which they arose and facilitates virus spread. The progeny virions can infect other cells or can be transmitted to another individual.




Figure 3. Schematic diagram depicting the replication cycle of influenza viruses. (Reproduced with permission from Fields Virology. Third edition. Lippincott Williams and Wilkins, Philadelphia [27]).Host range and interspecies transmission
Ducks and other waterfowl are the principal natural hosts of influenza A viruses (Figure 4), with all 15 HA and 9 NA virus subtypes circulating among them. Unlike in other species, influenza viruses target the gastrointestinal tract of waterfowl rather than the respiratory tract and the infections are almost without exception completely subclinical, some ducks shedding virus for as long as 30 days. This, together with the migratory behaviour of waterfowl and the ability of influenza viruses to persist in cold lake water, contributes to the fact that waterfowl form an immense reservoir for influenza viruses in nature. From this natural reservoir viruses are sometimes transmitted to other host species in which they less often continue spreading and sporadically cause high mortality. There are reports of direct virus transmission from waterfowl to pigs, horses, mink, domestic poultry and aquatic mammals, with associated infections of varying severity.7, 9, 35]. Six out of eighteen people to become infected died. The same H5N1 virus caused an influenza outbreak on Hong Kong’s chicken farms and resulted in a high mortality of birds. In an attempt to eradicate the disease, all of Hong Kong’s poultry (approximately 1.5 million birds) were slaughtered, which may well have prevented adaptation of the avian H5N1 virus to man and, thus, a subsequent human pandemic. Another example of direct interspecies transmission of a virus was reported recently when an H9N2 virus of avian origin infected two children in Hong Kong and five people in China. Perhaps the greatest threat these infections pose is the risk of a dual infection with a human influenza virus. The result can be a reassortant virus with H5 or H9 haemagglutinin, combined with all or some of the genes from the human virus, thereby enabling transmission between humans (see below).


Occasionally, avian-derived influenza A viruses are transmitted directly to man and one recent example is the H5N1 virus isolated in 1997 from patients in Hong Kong [



 Figure 4. Schematic diagram to show the natural reservoir of influenza A viruses and the interspecies transfer of the virus. It is hypothesised that wild aquatic birds are the primordial reservoir of all influenza A viruses and interspecies transmission of the virus is known to have occurred from pigs to man, and vice versa, and from poultry to man. There is also extensive evidence of transmission between other species. (Adapted with permission from Murphy and Webster, 1996. In Fields Virology. Third edition. Lippincott Williams and Wilkins, Philadelphia [27]).It remains uncertain which of the influenza virus proteins restrict host range. The available evidence indicates it is a polygenic trait and the receptor specificity of HA is considered an important determinant. Although influenza A viruses uniformly recognise cell surface oligosaccharides with a terminal sialic acid, their receptor-specificity varies. Most avian and equine viruses preferentially bind to the N-acetylneuraminic acid-2,3-galactose (NeuAc2,3Gal) linkage on sialyloligosaccharides, while human and swine influenza viruses prefer the NeuAc2,6Gal linkage. Some amino acid substitutions responsible for this difference in receptor specificity have been identified. Substitutions identified in H1 were also found in early isolates of H1N1 human and swine viruses, suggesting they are important for the generation of H1 human pandemic strains [24]. It has also been proposed that the NP is a major determinant in host range restriction.



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