Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus

Abstract

The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia, Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of unique AASs were reported simultaneously on different continents.

Molecular Epidemiology and Evolutionary Dynamics of Human Influenza Type-A Viruses in Africa: A Systematic Review

“…All pH1N1pdm09 strains sampled in Uganda, Senegal, Mauritania, Kenya, and South Africa had V106I and N248D in the catalytic site (CS) of their N1 proteins relative to the A/California/07/2009(H1N1) strain [ 47 , 48 , 54 , 55 , 56 , 104 ]. Quiliano et al observed 26 unique substitutions among N1 proteins of 59 Africa H1N1pdm09 strains sampled between 2009 and April 2011, with the highest frequency of substitutions in the transmembrane (TM) and L21 domains [ 64 ]. Kenya pH1N1pdm09 strain nucleoproteins (NP) and matrix protein (M1 and M2) sequences sampled in 2009 were 98.8–99.6% and 98–100%, similar to the A/California/07/2009(H1N1) strain, respectively.…”

“…A total of 90% of global H1N1 strains sampled between 2008 and 2009 were oseltamivir-resistant but sensitive to zanamivir [ 122 ]. Oseltamivir-resistant H1N1pdm09 strains were sporadically circulated in South Africa [ 43 ], globally between 2009 and 2011 [ 64 , 95 , 122 ], the Middle East and North Africa in 2015 [ 91 ], and Myanmar in 2017 [ 129 ]. However, there is no sufficient evidence that the resistant H1N1pdm09 variants resulted from oseltamivir treatment.…”

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“…In addition, the poor coverage of vaccination makes the prophylaxis of influenza ineffective. The mutation of neuraminidase (NA) also created a lot of oseltamivir-resistant influenza strains;39 hence, reinforcing development of new prophylactic and therapeutic tools is necessary according to the surveillance results of annual influenza epidemic.…”