Excerpts from: Characterization of conserved properties of hemagglutinin of H5N1 and human influenza viruses: possible consequences for therapy and i

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Here we show that the HA subunit 1 (HA1) of H5N1 viruses encodes specific and highly conserved information which may determine the recognition and targeting of these HPAI viruses to their receptor. The comparison with seasonal strains suggests that a subset of H5N1 in Egypt may be evolving towards an H1N1-like receptor usage.
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Despite its low infectivity for humans, there has been evidence in Egypt of several
clusters of human-to-human transmission with very high mortality rate. ISM analysis of 95 HA sequences from Egypt 2006 and 2007 showed that these viruses can be divided into two groups. Consensus IS of a first group (Egypt-1) of 55 strains contains a dominant peak of the frequency F(0.076) which is characteristic for H5N1 HA1 and a less prominent peak of the frequency F(0.236) which is characteristic for H1N1 HA1
(Figure 2a). In contrast, consensus IS of the second group (Egypt-2) (Figure 2b), which includes 40 H5N1 HA1, contains only one significant peak of the frequency F(0.236) corresponding to the consensus IS of H1N1 HA1 in Figure 1d. Figures 2c and 2d show representative IS of individual strains of both groups. Of H5N1 viruses which were isolated in Egypt during 2006, 76% belong to the group Egypt-1, and 24% were from the group Egypt-2. In contrast, in 2007, 48% belong to the Egypt-1 and 52% to Egypt-2. Figure 4 shows the IS spectra of peptide VIN1 and of the domains identified by consensus IS of H1N1, H3N2, H5N1 and H7N7 viruses (Table 2) and the position of these domains in the molecule. As can be seen, the receptor targeting site of H5N1 virus from the group Egypt-1 (A/Egypt/0636-NAMRU3/2007) is closer to the receptor binding site than in the other viruses of Figure 4. It may be speculated that this may affect the efficacy of the virus/receptor interaction.

Finally, we compared informational properties of H1N1 pandemic strains from 1918
from GenBank and seasonal H1N1 strains. The consensus IS of these pandemic isolates (Figure 3) is characterized by a dominant peak of the frequency F(0.258) which is different from the frequency F(0.236) characteristic of other seasonal flu H1N1 isolates (Figure 1d). Table 2 shows the domain corresponding to the frequency F(0.258). In the model of A/South Carolina/1/18 (Figure 4i) the position of this domain does not overlap with the corresponding domain of other seasonal H1N1 strains, but overlaps with the corresponding domain of Egypt-2 H5N1 viruses.
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H5N1 already replicates efficiently in humans, and cause case fatality rates that are ten times higher than those seen in the 1918 pandemic. Thus, an infectivity of H5N1 similar to seasonal flu would cause a catastrophic pandemic. The main obstacle for this worst case scenario is poor human-to-human transmission of H5N1 viruses, which is attributed to the paucity of sialic acid a2,3 receptor in the epithelium of the human upper respiratory tract, and the inability of the virus to replicate efficiently at this site. Interestingly, the ISM approach identifies important differences between H5N1 viruses from Egypt. Some have the characteristics of most H5N1 strains whereas about one third of the viruses display characteristics that are also found in human H1N1 seasonal virus. Interestingly the proportion of the latter viruses has increased from 25 to about 50: between 2006 and 2007.

Similarly the results of H5N1 strains from Egypt (Figure 2) may be indicative of a
possible viral evolution towards receptor usage similar to that of H1N1 viruses, which
efficiently replicate in the upper respiratory tract. The protein domain, which seems to be involved in this subtle change, corresponds to amino acid domain 99-132 (Figure 4g).

However, the role of this domain for enhanced infectivity in humans remains elusive.
Interestingly the corresponding domain of Spanish flu viruses and Egypt-2 H5N1 viruses are much closer to the receptor binding site of HA1 than in all other H1N1 and H5N1 viruses (Figures 4e-4i and Table 2). This closer proximity may indicate more efficient virus/receptor interactions in these influenza viruses.
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