Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors

Abstract

H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid-alpha2,6-galactose (SAalpha2,6Gal), whereas the latter prefer those ending in SAalpha2,3Gal (refs 3-6). A conversion from SAalpha2,3Gal to SAalpha2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.

Structure and receptor-binding properties of an airborne transmissible avian influenza A virus hemagglutinin H5 (VN1203mut)

“…H1, H2 and H3 (Stevens et al, 2004;Tumpey et al, 2007). However, the H5 HA structural adaptation to the human receptor binding requires further defi nition (Yamada et al, 2006). It has been shown that experimental changes at position 226 and 228 (H3 numbering) in H5 resulted in the recognition of humantype receptors (Stevens et al, 2006).…”

Molecular epidemiological surveys of H5 subtype highly pathogenic avian influenza viruses in poultry in China during 2007-2009

“…This indicated that they were highly pathogenic (Senne, et al, 1996). None of them carried the mutations 129AV, 134AV, 182AK, 192AR, 222AL, 223AN or 224AS (H5 numbering) in the HA gene, which could render the virus binding to human SAa2,6Gal receptors and facilitate the virus replicate efficiently in humans (Auewarakul et al, 2007;Stevens, et al, 2006;Yamada et al, 2006).…”

Prediction of specific virus outbreaks made from the increased concentration

“…The first synthetic replikins pan-influenza vaccine was successful against H5N1; it also blocked virus excretion, providing for the first time the potential to block the development of H5N1 reservoirs (Table II and Figure 3a) is here shown to occur in advance of and during the pandemic. This change is concomitant with changes from neutral to acidic conformation assisting fusion of the virus with the host membrane during virus entry (27)(28)(29)(30). The actual visualization of Replikins, with the ability to count them, supports the reality and practical clinical relevance of Replikin structures.…”

“…The central role of the sialic acid receptor for influenza virus entry into host cells was demonstrated a) in 1959 by the authors by blocking the virus entry into brain cells by sialic acid conjugates from brain gangliosides (25), and b) by the release of similar sialic acid conjugate decoys (sialoresponsins) by the chorioallantoic membrane of the chick egg under influenza attack (26). The molecular definition of the reaction between the hemagglutinin unit and the sialic acid receptor pocket of the host membrane was recently demonstrated (27)(28)(29)(30).…”