The pandemic H1N1 2009 virus evolved rapidly, with new mutations that are likely to provide the viral strain with more opportunities to survive and spread (Fitch et al., 1991
). Although many mutations are found in H1N1pdm viruses, only a few mutations were reported to benefit the new viruses in terms of host receptor binding, virulence, and drug resistance (), which will be discussed below.
Mutations of the pandemic (H1N1) virus and their associated functions
The hemagglutinin (HA) segment plays an essential role in viral cell entry. It has been found that viral strains with residues D190/D225 are human-specific, D190/G225 swine-specific, and E190/G225 avian-specific. The H1N1pdm HA has D190/D225, supporting the efficient transmissibility of these viruses among humans (Potdar et al., 2010
). A mutation (D225G/E) was found in the HA protein in the pandemic virus; this may allow the virus to have dual hosts, humans and swine (Chen et al., 2010
). Our structural analyses of the H1N1pdm HA reveals that this virus is closer to the 1918 H1N1 pandemic viruses than to seasonal H1N1 influenza viruses, suggesting the preexisting immunity against the 2009 H1N1pdm viruses in elderly persons () (Xu et al., 2010
). Significant amino acid differences occur in the four antigenic regions (Sa, Sb, Ca and Cb) of HA when comparing the pandemic and seasonal influenza viruses. High sequence similarity (~80%) was found between the two pandemic viruses (1918 and 2009), with the differences restricted mainly to the Ca region of HA. This agrees with the findings of Booy et al. (2009)
, Morens et al. (2010)
, and Hancock et al. (2009)
that cross-reactive antibodies to H1N1pdm do exist in older people.
Figure 4 Structural alignment of the HA segment of three different influenza A H1N1 viruses showing a mutation at position D222G. The different chains: red, grey, and yellow, show the different subunits of the HA trimer. Antigenic regions of HA are also color (more ...) Hancock et al. (2009)
used microneutralization assays to test for level of antibody response to H1N1pdm in serum samples from various age groups, both before and after vaccination with seasonal flu vaccine. They did not find any cross-protective pre-existing immunity against H1N1pdm in pediatric or younger-adult age groups, but for those aged 60 years or older, even before seasonal flu vaccination, they did find a significant cross-protective immunity. Seasonal flu vaccination produced no measurable change in antibody titers against H1N1pdm.
A single residue in the PB2 subunit of the influenza polymerase, amino acid 627, regulates polymerase activity in a species-specific fashion, with a lysine(K) mainly found in human viruses and a glutamic acid (E) in avian viruses (Subbarao et al., 1993
). PB2 K627 also correlates with enhanced polymerase activity and mortality in mammals (Steel et al., 2009
), and moderately enhanced replication in pigs, consistent with pigs serving as an intermediary viral reservoir between birds and humans (Manzoor et al., 2009
). The current pandemic (H1N1) 2009 virus was found to exhibit mainly K627, resulting in high levels of viral replication in human cells. Other changes within PB2, such as the D701N mutation, are associated with increased host range, polymerase activity, and pathogenicity in mammalian systems and humans (Doudnaa and Mehle, 2009
). An in vitro experiment using cell cultures in a mouse model does not support that PB2-E627K or D701N mutations are responsible for enhanced virulence of the pandemic virus (Jagger et al., 2010
). Additionally, a mutation has been linked to increased transmissibility or infectivity, namely, the valine to isoleucine V100I mutation in the NP segment, which was found to occur during the short period of time between pandemic alert levels phase 4 and phase 6 (Pan et al., 2010
Concerning drug resistance, nearly all of the 2009 pandemic H1N1 viruses were sensitive to neuraminidase inhibitors; only sporadic Oseltamivir-resistant viruses with the H275Y mutation in the NA segment were reported. On the contrary, Oseltamivir was found more effective for pandemic (H1N1) 2009 than for seasonal H1N1 influenza with or without the H275Y mutation (Ikematsu et al., 2010
). Additionally, the mutation I222V that has been shown to affect susceptibility to neuraminidase inhibitors (Deyde et al., 2010
; Monto et al, 2006
) was also detected in a North Carolina pandemic specimen (A/North Carolina/15/2009). The pandemic virus contains the adamantine resistance-conferring change S31N in the M2 protein (Dawood et al., 2009; Deyde et al., 2010
; Garten et al., 2009