The hemagglutinin of the influenza A(H1N1)pdm09 is mutating towards stability

Abstract

The last influenza A pandemic provided an excellent opportunity to study the adaptation of the influenza A(H1N1)pdm09 virus to the human host. Particularly, due to the availability of sequences taken from isolates since the beginning of the pandemic until date, we could monitor amino acid changes that occurred in the hemagglutinin (HA) as the virus spread worldwide and became the dominant H1N1 strain. HA is crucial to viral infection because it binds to sialidated cell-receptors and mediates fusion of cell and viral membranes; because antibodies that bind to HA may block virus entry to the cell, this protein is subjected to high selective pressure. Multiple alignment analysis of sequences of the HA from isolates taken since 2009 to date allowed us to find amino acid changes that were positively selected as the pandemic progressed. We found nine changes that became prevalent: HA1 subunits D104N, K166Q, S188T, S206T, A259T, and K285E; and HA2 subunits E47K, S124N, and E172K. Most of these changes were located in areas involved in inter- and intrachain interactions, while only two (K166Q and S188T) were located in known antigenic sites. We conclude that selective pressure on HA was aimed to improve its functionality and hence virus fitness, rather than at avoidance of immune recognition.

Molecular epidemiology survey and characterization of human influenza A viruses circulating among Palestinians in East Jerusalem and the West Bank in 2015

“…Substitution I321V is also a common variant marker within outbreaks [12] and was found in all Palestinian isolates. E47K , S124K , and E172K substitutions located in the HA2 do not only define clade 6B; they were reported, along with other substitutions, to increase HA stability through generation of favorable inter- and intramonomer interactions [39]. A variant with E47K was also shown to induce infection in ferrets [40].…”

H1N1 influenza viruses varying widely in hemagglutinin stability transmit efficiently from swine to swine and to ferrets

“…Given that human influenza A viruses prefer a stable HA protein but many zoonotic viruses have an HA protein that is relatively unstable [ 35 , 39 ], it is important to identify the evolutionary pathways by which an unstable HA could acquire increased stability. The 2009 pH1N1 pandemic virus most likely evolved by a stepwise stabilization pathway, as HA acid stability progressively increased during the evolution of H1N1 from swine precursors (pH 5.5–6.0) and early 2009 human isolates (pH 5.5) to later human isolates (pH 5.2–5.4) [ 35 , 39 , 45 , 64 , 65 ]. The surveillance results reported here show that post-2009 swine H1 viruses have a broad range of HA activation pH (5.1–5.9), and experimental infections in pigs show that a pH1N1 virus with an HA activation pH of 5.3 is readily transmitted between swine and from swine to ferrets without attenuation, fixed mutations, or a change in its HA acid stability.…”

“…In ferrets, a more stable HA protein (activation pH < 5.6) is needed for efficient upper respiratory tract growth and airborne transmissibility of H5N1 [ 36 , 37 , 43 , 44 ] and pH1N1 viruses [ 39 ]. Furthermore, a stable HA protein has also been linked to pH1N1 pandemic potential and adaptation to humans [ 39 , 45 ].…”

Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses

“…As previously mentioned, influenza A exhibits antigenic drift/shift phenomena resulting from the HA protein's ability to undergo rapid evolution because of the plasticity of the viral RNA-dependent RNA polymerase. It is believed that mutations occurring in the HA protein, including reassortments and mutations among animals and humans, were the drivers of previous pandemics (38).…”

“…Adaptive mutations can lead to a number of phenotypic changes, including variations in antigenicity, increased diversity in viral protein sequences, the ability to avoid antibody pressure, receptor preference, virulence, altered fusion functionality, and evasion of the immune response. Rapid modifications can give rise to new strains with features that are different from any viruses that have previously been confronted, potentially causing another epidemic/pandemic (38).…”