Evolution Of The Influenza Virus

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There are three Influenza viruses groups, A, B and C, which are part of the Orthomyxoviridae family of (-) strand RNA viruses. These viruses are segmented containing 8 separate gene segments within a nucleocapsid protein (Neumann, G. et al. 2009). The 8 genes in the influenza viral genome encode 11 proteins: two nonstructural proteins (NS1 and NS2), four transcriptase proteins (PB1, PB2, PB1-F2, and PA), two surface glycoproteins (HA and NA), two matrix proteins (M1 and M2) and one nucleocapsid protein (NP) (Kian-Meng Goh, G. 2009; Chen, Ji-Ming, et al. 2009). Segment 1 encodes for the PB2, segment 2 encodes for PB1, segment 3 encodes for PA, segment 4 encodes the HA gene, segment 5 encodes the NP gene, segment 6 encodes the NA gene, segment 7 encodes the M genes and segment 8 encodes the NS genes. Figure 1 shows the schematic representation of the influenza A virion (McHardy, Alice C. and Ben Adams. 2009).

Figure 1. Schematic representation of an influenza A virion (McHardy, Alice C. and Ben Adams. 2009).

The influenza A virion is a globular particle sheathed in a lipid bilayer derived from the plasma membrane of its host. Two integral membrane proteins, HA and NA, are studded in the lipid bilayer creating a spike-shaped structure (Kian-Meng Goh, G. 2009). The HA (haemagglutinin) gene, is divided into 16 subtypes (H1-H16) and the NA (neuramidase) gene divided into 9 subtypes (N1 - N9). Most of the 16 HA and 9 NA subtypes have evolved into some distinct lineages and sublineages (Liu, S. 2009; Kian-Meng Goh, G. 2009; Ghedin, E., et al. 2009) The HA subtypes or variants retain the capacity to attach the influenza virus to the host cells, but the difference in the subtypes allows the influenza virus to evade host's immune system by fooling it (Watts, Geoff. 2009).

The hemagglutinin is a major surface glycoprotein that attaches the influenza virus to the sialic acid residues on the host's cell surface. The hemagglutinin fuses the viral membrane envelope to the host's cell membrane, allowing the viral genome to enter into the cell (McHardy, A.C., and Ben Adams. 2009). Human influenza viruses' hemagglutinin recognizes the host- cell receptors containing sialyloligosaccharides with an N-acetyl sialic acid linked to galactose with an α2,6 linkage at the end. Avian viruses prefer an α2,3 linkage, while pigs tend to contain both α2,6 and α2,3 linkages (Horimoto, T. and Yoshihiro Kawaoka. 2005).

Another surface glycoprotein, neuraminidase, cleaves the terminal sialic acid residues from glycoproteins and glycolipids on the host cell surface thereby releasing any budding viral particles from the infected cell. The host's immune response recognizes and targets the hemagglutinin because the hemagglutinin is about 5 times more prevalent than the neuraminidase in the viral membrane (McHardy, A.C., and Ben Adams. 2009).

The HA and NA genes each contain about 5 antigenic domains, called epitopes, that tend to be recognized by antibodies as well as having the most prominent mutations. These mutations can reduce or inhibit the binding of antibodies and inhibit the interaction of antiviral drugs with the influenza virus. It is these mutations that allow for new subtypes to be created and antigenic drift to occur (Gurtier, Lutz. 2009; Ghedin, E. et al. 2009; McHardy, A.C. and Ben Adams. 2009). The NA subtypes are found in combination with the HA to create a variety of different strains (Watts, Geoff. 2009).

Before 1889, the primary type of influenza virus was from the H1 family, while after 1889 new types of influenza began to circulate. After 1889 a new strain of H2 influenza began spreading throughout Russia, replacing the H1 influenza strain in humans (MacKenzie, D, and M. Marshall. 2009). In 1918-1919, a new strain caused by H1N1 known as "Spanish Influenza" began to spread, becoming an epidemic. Those who had the influenza of 1889 or before seemed to have obtained some immunity to the 1918-1919 influenza strain. This enhanced virulence in the influenza may have been due to a mutations or reassortment in the 8 gene segments that make up Influenza (Taubenberger, J. 2006; Nelson, M., et al. 2008).

Since the 1918-1919 "Spanish Influenza" epidemic, there have been numerous influenza outbreaks, each involving a different unique strain. In 1931, the swine flu was isolated from a pig in Iowa, and in 1933 the first human "Swine" flu was isolated in London (MacKenzie, D, and M. Marshall. 2009). In 1957, the influenza virus evolved into H2N2 strain displacing the H1N1 viruses previously circulating in humans. The 1957 virus was also called the "Asian" flu and the beginning of a new pandemic. In 1968, the "Hong Kong" flu, a new influenza strain H3N2, created a new pandemic. The "Hong Kong" flu differed from the H2N2 virus by only the hemagglutinin protein. Those individuals infected by the 1957 influenza strain seemed to have some immunity to the H3N2 strain (MacKenzie, D and M. Marshall. 2009; Nelson, M., et al. 2008).

Graham Laver and Robert Webster discovered in 1972 that avian waterfowl was a natural host for the influenza virus. These strains could reassort with human strains leading to new human strains that may possibly become more virulent than the current strain. (MacKenzie, D, and M. Marshall. 2009). From 1976 - 2009, several H1N1 viruses appeared that seemed to have jumped from pigs to humans. The newest H1N1 virus in 2009 triggered panic that another 1918 pandemic might occur sometime in the near future. Table 1 shows the evolution of the swine influenza A virus from 1918 until 2009. The question(s) that is often asked for the influenza virus is why there are so many different types or strains of influenza and is it due to "shifts" and "drifts" or recombination and reassortment?

Table 1: Evolution of swine influenza A virus (Hajjar, S. and Kenneth McIntosh. 2010).

1918 - 1919




H1N1 pandemic also affected swine.



The first isolate of H1N1 in pigs.



H3N2 infect swine in Asia after human pandemic


Outbreak of new H1N1 swine strain of



A/New Jersey/1976 occurred in military



personnel at Fort Dix, New Jersey.



Triple reassortant viruses were isolated from pigs.

1958 - 2005

37 human swine-origin influenza were reported.


11 sporadic triple reassortant swine influenza


viruses were reported in human.



New quadruple reassorted swine influenza


H1N1 strain (A/California/07/2009) emerged


in human populations and caused global influenza pandemic.








Influenza A viruses are highly varied due to natural point mutations, cross-host transmissions and genomic segment re-assortment among and within the subtypes, lineages and sublineages (Chen, J-M. et al. 2009) Antigenic drift" is when minor mutations occur in the H and N proteins leading to slow, but significant changes in antigenicity over time. This may be due to the influenza virus having poor proofreading abilities causing numerous errors in progeny genes leading to frequent mutations. "Antigenic Shift" is due to more substantial subtype changes of the H1 and H2 variety in a shorter time with or without similar changes in the N gene. "Antigenic shift" occurs when new H or N gene segments are acquired by a process called "reassortment" (Hajjar, S. and Kenneth McIntosh. 2010; McHardy, A.C., and Ben Adams. 2009; Ghedin, E., et al. 2009). The differences and reasons for "antigenic shift" and "antigenic drift" are displayed in table 2.

Table 2: Antigenic drift and shift








Minor change within subtype


Major change, new subtype

Point mutations

Exchange of gene segments

Occurs in A and B subtypes

Occurs in A subtypes only

May cause epidemics

May cause pandemics

Ex: A/Fujian (H3N2) replaced

Ex: H3N2 replaced H2N2 in 1968

A/Panama (H3N2) in 2003-2004




(Hajjar, S. and Kenneth McIntosh. 2010).

Shuffling of gene segments occurs if two or more different subtypes of influenza A virus infect the same host cell, usually in swine. Susceptible swine cells have receptors for both avian and human influenza strains. Pigs serve as mixing vessels for exchanging of genetic material between human and avian viruses creating new novel subtypes, as shown in figures 2 and 3 (McHardy, A.C. and Ben Adams. 2009). All 16 HA antigens and 9 NA antigens are found in avian water fowl, while only H1-H3 and N1-N2 viral subtypes are found in humans. Gene segment shuffling leads to antigenic changes creating new viral subtypes (Kian-Meng Goh, G., et al. 2009).

Figure 2. Generation of genetic diversity and antigenic drift in the evolution of human influenza A viruses.

Blue and yellow viruses depict two antigenically similar strains of the same subtype circulating in the human population. The genetic diversity of the circulating viral population increases through mutation and reassortment. Single white arrows indicate relationships between ancestral and descendant viruses. White marks on the segments indicate neutral mutations and red marks indicate mutations that affect the antigenic regions of the surface proteins. Incoming pairs of orange arrows indicate the generation of reassortants with segments from two different ancestral viruses. As these viruses continue to circulate, immunity against them builds up in the host population, represented here by the narrowing of the bottleneck. In parallel, viruses with mutations affecting the antigenic regions of the surface proteins accumulate in the viral population. At some point a novel antigenic drift variant, indicated by a red colored virus, which is less affected by immunity in the human population, is generated. This variant is able to cause widespread infection and founds a new cluster of antigenically similar strains. (McHardy, Alice C. and Ben Adams. 2009).

Fig. 3 Genesis of swine-origin H1N1 influenza viruses.

In the late 1990's, reassortment between human H3N2, North American avian, and classical swine viruses resulted in triple reassortant H3N2 and H1N2 swine viruses that have since circulated in North American pig populations. A triple reassortant swine virus reassorted with a Eurasian avian-like swine virus, resulting in the S-OIV that are now circulating in humans (Neumann, G., Noda T., and Y. Kawaoka. 2009.)

The 1918 Spanish Influenza developed in three waves: "first wave" in spring (March thru April) of 1918, "second wave" in fall (September thru November) of 1918, and finally the "third wave" in early 1919. During the time between the first and second waves, a mutation or reassortment possibly occurred that made the Spanish influenza significantly more virulent (Tanbenberger, J. 2006). The H1N1 virus of 1918 contained antigenically novel hemagglutinin protein, which most humans and swine were susceptible to. The NA protein was also replaced during antigenic shifting before the pandemic started. Sequence and phylogenetic analyses suggests that both surface proteins were derived from an avian-like influenza and that the precursor virus did not circulate widely before 1918 (Tanbenberger, J. 2006). There are regression analyses that suggest that the progenitor of the 1918 virus may have entered the human population as early as 1915 (Reid,A., et al. 2004). The H1N1 influenza virus circulated within the human population from 1918 - 1957 and again from 1977 to the present.

In 1947 a major antigenic change, where numerous nucleotide and amino acid differences in the antigenic regions of the hemagglutinin (HA), occurred due to antigenic divergence. The changes in the antigenic regions of the hemagglutinin created an epidemic in 1950-1951, without any changes in the actual antigenic subtype, A/H1N1, is called intra-subtype assortment (Nelson, M. et al. 2008). The PB1, NA and M segments of the 1947 virus were from A/H1N1 and combined with novel PB2, PA, HA, NP and NS gene segments. Then in 1951, genomic reassortment took place between novel PB1, PA, NP, NA, M and NS gene segments combined with older PB2 and HA genes (Nelson, M. et al. 2008). This epidemic occurred in the United Kingdom and Canada and the mortality levels exceeded that of both the 1957 and 1968 pandemics, without a change in antigen subtype,

Another genomic reassortment occurred in 1957, where the HA (H2), NA (N2) and a viral RNA polymerase gene segment PB1 from an avian influenza virus merged with other gene segments from a previously circulating human H1N1 influenza virus (Horimoto, T. and Yoshihiro Kawaoka. 2005). The 1951 A/H1N1 disappeared only to be replaced with this new novel subtype H2N2 reassortant virus. Reassortants of the HA avian gene segment (H3) and PB1 avian gene segment again led to a novel influenza virus in 1968, H3N2. H3N2 displaced the H2N2 and still circulates today alongside an H1N1 that emerged in 1977 (McHardy, A.C., and Ben Adams. 2009; Horimoto, T. and Yoshihiro Kawaoka. 2005). Both the 1957 and 1968 strains contained avian genes encoding for PB1 and HA, indicating that these two genes interact functionally, either at a protein or nucleic acid level to enhance the replicative ability of the hybrid viruses (Horimoto, T. and Yoshihiro Kawaoka. 2005).

The reemergence of human H1N1 influenza viruses in 1977 was due to a laboratory error when the virus was released from a laboratory freezer. The H1N1 virus has been circulating endemically and epidemically from 1918 until 1957 and again from 1977 until the present (Taubenberger, J.K. and David M.Morens. 2006). In 1998, the classical swine influenza viruses reassorted with the human H3N2 influenza virus producing triple reassortants H3N2 swine virus (rH3N2). It has also believed that further triple reassortment between rH3N2 and classical swine H1N1 viruses generates new reassortant swine A/H1N1 and A/H1N2 viruses (Garten, R.J., et al. 2009).

Two distinct H3N2 influenza viruses were isolated from swine in late 1998 in several states that were either double reassortant viruses or triple reassortants. The double reassortant contained HA, Na and PB1 similar to those of human H3N2 influenza viruses and M, NP, NS, PA and PB2 similar to those of classical H1N1 swine influenza viruses. The triple reassortant were more complex in that they contained HA, Na and PB1 of human influenza viruses, M, NP and NS or classical swine H1N1 as well as PA and PB2 of avian influenza viruses. Only the triple reassortant virus was established in the swine population and continued to circulate and evolve (Brockwell-Staats, C., et al. 2009; Smith, G.J.D. et al. 2009; Hay, A.J., et al. 2001).

Since 1998, the original H3N2 strain along with variants of the original triple H3N2 triple reassortant virus have been co-circulating in swine alongside the H1N1 virus. Occasionally, the swine H1N1 crosses into the human population, which has been confirmed to have occurred 43 times from 1974 to 2005. From December 2005 through February 2009, 11 human infections with swine influenza H1N1 or H1N2 were reported to the CDC (Brockwell-Staats, C., et al. 2009; Shinde, V. et al. 2009).

In April 2009, a new H1N1 virus originating from swine influenza A viruses was isolated from humans in both Mexico and the United States. This new H1N1 virus threw the world into a panic at the thought of a possible appearance of a similar pandemic to the 1918 Spanish influenza pandemic. Scientist hurried to determine what the genetic sequence of the virus was and where the gene segments came from. The virus was determined to contain combinations of gene segments that had not been seen in swine or human influenza viruses in the US or elsewhere before. The NA and M gene segments were determined to be from the Eurasian swine genetic lineage, while the HA, NP and NS gene segments are from a classical swine lineage. The PB2, and PA gene segments are from the swine triple reassortant lineage, the American H3N2 avian virus. The PB1 gene segment, in the new H1N1 of 2009, had started in swine entered human and birds around 1968 from the H3N2 strain (Garten, R.J., et al. 2009; McHardy, A.C. and Ben Adams. 2009; Hajjar, S. and Kenneth McIntosh. 2010; Neumann, G. et al. 2009 ). Figure 4 and figure 5 shows the host and lineage for the gene segments of the 2009 A/H1N1 virus (Garten, R.J., et al. 2009; Hajjar, S. and Kenneth McIntosh. 2010).

Fig. 4 Host and lineage origins for the gene segments of the 2009 A(H1N1) virus: PB2, polymerase basic 2; PB1, polymerase basic 1; PA, polymerase acidic; HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; M, matrix gene; NS, non-structural gene (Garten, R.J., et al. 2009).

Figure 5. 2009 Influenza A (H1N1) virus genotype (Hajjar, S. and Kenneth McIntosh. 2010).

The 2009 swine H1N1 influenza virus has been determined to contain one of the swine genes from the original 1918 human influenza virus. This means that the 2009 strain is a fourth generation descendant of the 1918 virus (Hajjar, S. and Kenneth McIntosh. 2010; McHardy, A.C. and Ben Adams. 2009). Each of the influenza pandemics/epidemics shows that reassortment or "antigenic shift" of the hemagglutinin with or without neuraminidase, along with cross-species introduction into humans from swine (and occasionally avian) can occur as a single event or multiple events from genetically similar viruses. The other six gene segments have been determined to have undergone reassortment that may affect the influenza virus in several ways, but mainly by increasing the virulence or pathogenicity of the virus. Some of the gene segments have changed due to alterations in the nucleotides or amino acids causing minor changes in the genes through "antigenic drift." Swine also play a significant role as an intermediate host in the cross-species introduction of new strains from avian to swine to humans. The influenza strains that emerge through the use of swine as an intermediate host are through genetic reassortment and the formation of novel human viruses (Hay, A.J, et al. 2001).The WHO and CDC will keep monitoring the world for outbreaks, possible epidemics and pandemics to determine any potential novel human influenza occurrences that may turn into pandemics.