Dataset Information

Compensatory evolution of net-charge in influenza A virus hemagglutinin.

ABSTRACT: The propagation of influenza A virus depends on the balance between the activities of hemagglutinin (HA) for binding to host cells and neuraminidase (NA) for releasing from infected cells (HA-NA balance). Since the host cell membrane and the sialic acid receptor are negatively charged, the amino acid substitutions increasing (charge+) and decreasing (charge-) the positive charge of HA subunit 1 (HA1) enhance and reduce, respectively, the binding avidity and affinity. The positive charge of HA1 in human influenza A virus bearing subtype H3N2 (A/H3N2 virus) was observed to have increased during evolution, but the evolutionary mechanism for this observation was unclear because this may disrupt the HA-NA balance. Here we show, from the phylogenetic analysis of HA for human A/H3N2 and A/H1N1 viruses, that the relative frequencies of charge+ and charge- substitutions were elevated on the branches where the number of N-glycosylation sites (NGS) increased and decreased, respectively, compared to those where the number of NGS did not change. On the latter branches, the net-charge of HA1 appeared to have been largely maintained to preserve its structure and function. Since the charge+ and charge- substitutions in HA1 have opposite effects to the gain and loss of NGS on the binding and release of the virus, the net-charge of HA1 may have evolved to compensate for the effect of the gain and loss of NGS, probably through changing the avidity. Apparently, the relative frequency of charge- substitutions in HA1 of A/H3N2 virus was elevated after the introduction of oseltamivir, and that of charge+ substitutions in HA1 of A/H1N1 virus was elevated after the spread of oseltamivir resistance. These observations may also be explained by the compensatory effect of the net-charge in HA1 on the NA activity for keeping the HA-NA balance.

SUBMITTER: Kobayashi Y

PROVIDER: S-EPMC3395715 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Compensatory evolution of net-charge in influenza A virus hemagglutinin.

Kobayashi Yuki Y Suzuki Yoshiyuki Y

PloS one 20120712 7

The propagation of influenza A virus depends on the balance between the activities of hemagglutinin (HA) for binding to host cells and neuraminidase (NA) for releasing from infected cells (HA-NA balance). Since the host cell membrane and the sialic acid receptor are negatively charged, the amino acid substitutions increasing (charge+) and decreasing (charge-) the positive charge of HA subunit 1 (HA1) enhance and reduce, respectively, the binding avidity and affinity. The positive charge of HA1 i ...[more]

PMID: 22808159

Similar Datasets

Project description:The nucleotide and amino acid sequences of 40 influenza virus hemagglutinin genes of the H3 serotype from mammalian and avian species and 9 genes of the H4 serotype were compared, and their evolutionary relationships were evaluated. From these relationships, the differences in the mutational characteristics of the viral hemagglutinin in different hosts were examined and the RNA sequence changes that occurred during the generation of the progenitor of the 1968 human pandemic strain were examined. Three major lineages were defined: one containing only equine virus isolates; one containing only avian virus isolates; and one containing avian, swine, and human virus isolates. The human pandemic strain of 1968 was derived from an avian virus most similar to those isolated from ducks in Asia, and the transfer of this virus to humans probably occurred in 1965. Since then, the human viruses have diverged from this progenitor, with the accumulation of approximately 7.9 nucleotide and 3.4 amino acid substitutions per year. Reconstruction of the sequence of the hypothetical ancestral strain at the avian-human transition indicated that only 6 amino acids in the mature hemagglutinin molecule were changed during the transition between an avian virus strain and a human pandemic strain. All of these changes are located in regions of the molecule known to affect receptor binding and antigenicity. Unlike the human H3 influenza virus strains, the equine virus isolates have no close relatives in other species and appear to have diverged from the avian viruses much earlier than did the human virus strains. Mutations were estimated to have accumulated in the equine virus lineage at approximately 3.1 nucleotides and 0.8 amino acids per year. Four swine virus isolates in the analysis each appeared to have been introduced into pigs independently, with two derived from human viruses and two from avian viruses. A comparison of the coding and noncoding mutations in the mammalian and avian lineages showed a significantly lower ratio of coding to total nucleotide changes in the avian viruses. Additionally, the avian virus lineages of both the H3 and H4 serotypes, but not the mammalian virus lineages, showed significantly greater conservation of amino acid sequence in the internal branches of the phylogenetic tree than in the terminal branches. The small number of amino acid differences between the avian viruses and the progenitor of the 1968 pandemic strain and the great phenotypic stability of the avian viruses suggest that strains similar to the progenitor strain will continue to circulate in birds and will be available for reintroduction into humans.

Project description:Seasonal influenza A viruses of humans evolve rapidly due to strong selection pressures from host immune responses, principally on the hemagglutinin (HA) viral surface protein. Based on mouse transmission experiments, a proposed mechanism for immune evasion consists of increased avidity to host cellular receptors, mediated by electrostatic charge interactions with negatively charged cell surfaces. In support of this, the HA charge of the globally circulating H3N2 has increased over time since its pandemic. However, the same trend was not seen in H1N1 HA sequences. This is counter-intuitive, since immune escape due to increased avidity (due itself to an increase in charge) was determined experimentally. Here, we explore whether patterns of local charge of H1N1 HA can explain this discrepancy and thus further associate electrostatic charge with immune escape and viral evolutionary dynamics. Measures of site-wise functional selection and expected charge computed from deep mutational scan data on an early H1N1 HA yield a striking division of residues into three groups, separated by charge. We then explored evolutionary dynamics of these groups from 1918 to 2008. In particular, one group increases in net charge over time and consists of sites that are evolving the fastest, that are closest to the receptor binding site (RBS), and that are exposed to solvent (i.e., on the surface). By contrast, another group decreases in net charge and consists of sites that are further away from the RBS and evolving slower, but also exposed to solvent. The last group consists of those sites in the HA core, with no change in net charge and that evolve very slowly. Thus, there is a group of residues that follows the same trend as seen for the entire H3N2 HA. It is possible that the H1N1 HA is under other biophysical constraints that result in compensatory decreases in charge elsewhere on the protein. Our results implicate localized charge in HA interactions with host cells, and highlight how deep mutational scan data can inform evolutionary hypotheses.

Dataset Information

Compensatory evolution of net-charge in influenza A virus hemagglutinin.

Publications

Compensatory evolution of net-charge in influenza A virus hemagglutinin.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets