Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites

Abstract

In this work, we study the consequences of sequence variations of the "2009 H1N1" (swine or Mexican flu) influenza A virus strain neuraminidase for drug treatment and vaccination. We find that it is phylogenetically more closely related to European H1N1 swine flu and H5N1 avian flu rather than to the H1N1 counterparts in the Americas. Homology-based 3D structure modeling reveals that the novel mutations are preferentially located at the protein surface and do not interfere with the active site. The latter is the binding cavity for 3 currently used neuraminidase inhibitors: oseltamivir (Tamiflu®), zanamivir (Relenza®) and peramivir; thus, the drugs should remain effective for treatment. However, the antigenic regions of the neuraminidase relevant for vaccine development, serological typing and passive antibody treatment can differ from those of previous strains and already vary among patients.This article was reviewed by Sandor Pongor and L. Aravind.

Pandemic swine influenza virus (H1N1): A threatening evolution

“…The HA gene has acquired a proline to serine substitution at position 200 thus has become slightly less virulent as compared to the 1918 (H1N1) virus. The NA gene, is also quite novel differing by 18.2% from the seasonal H1N1 virus which may be a possible reason that the available vaccines may not work effectively against the virus thereby increasing the demand for newly formulated vaccines in a short period of time [15,16].…”

Finding a new drug and vaccine for emerging swine flu: What is the concept?

“…87 According to the recent study by Maurer-Stroh and colleagues, the antigenic regions of the neuraminidase relevant for vaccine development, serological typing, and passive antibody treatment was totally different from those of classical influenza. 94 This is the main reason for asking why the vaccine for classical influenza cannot be applied for the novel strain and this is also the reason for the need for finding a new vaccine specific to the novel virus. 4.…”

“…93,94 According to the homology modeling of the neuraminidase, it can be seen that novel mutations are not likely to interfere with the active site hence the currently used neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) will still be effective against the new virus strain. 94 The same mechanism of pharmacological reaction, blocking M2, can be seen in either classical or novel viruses. However, the drugs do not have the same effect in both viruses.…”

“…Nevertheless, adding to the basic two major focuses, safety and efficacy, for seasonal influenza vaccine, the other two major focuses, immunogenicity and timely availability, are also needed for pandemic influenza vaccine. 94,95 However, the original seed virus must be the new virus. This raises the problem of production because it is hard to make the new virus available in huge amounts.…”

“…Although there is evidence on the finding of immunity to the new virus in some elderly adults, 63 this might be a cross-protective immunity since there are some antigenic similarities to currently or previously circulating strains of influenza. 94 There is currently no effective vaccine for swine flu. The classical influenza vaccine is not applicable.…”