Abstract
Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor-binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.
Highlights
The influenza viruses (IVs) have had an important effect on human history
There is one specified group of glycoproteins appearing on viral envelope that participates in the recognition and invasion, such as HA in IVs, gp160 in HIV and the spike (S) glycoprotein in the SARS coronaviruses [57,58]
At the very first stage, these proteins recognize a specified glycan pattern on the surface of the host cell; from this perspective, these glycoproteins can be deemed as a kind of lectin or glycan-binding protein (GBP)
Summary
The influenza viruses (IVs) have had an important effect on human history. Three influenza A pandemics have taken place in 1918–1919 (H1N1), 1957 (H2N2) and 1968 (H3N2), which killed up to 50 million people all over the world. IVs originated in waterfowl; due to antigenic mutations, including antigenic drift and antigenic shift, the mutation in the receptor-binding domains (RBDs) could result in a human pandemic similar to H1N1 [1]. There are increasing numbers of reports about avian IVs, such as the H5N1, H7N7 and H9N2 virus, that have infected humans [2,3]. As of 02 May 2012, 603 confirmed human cases with avian influenza H5N1 virus were reported to the WHO since 2003; of these patients, 356 died (fatality rate: 59.03%) [4]. Three RBDs at the tip of HA binding to the host sialoglycans are essential for endocytosis, each monomer can be cleaved by proteases in phagosome into a globular head and a stem region, known as HA1 and HA2, respectively [5,6]. Uncharacterized changes to its conformation pull the two membranes together [7,8]
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