Influenza hemagglutinin ha or haemagglutinin british english is a homotrimeric glycoprotein. Since 20, influenza h7n9 virus has caused five epidemic waves of human infection. Comparisons of residues between subtypes of influenza virus is increasingly used to assess the zoonotic potential of a circulating strain and for comparative studies across subtypes. Has of different subtypes are marked with their numbering according to h3. These substances are found in plants, invertebrates, and certain microorganisms. Conserved epitope on influenzavirus hemagglutinin head. Characterization of the receptor binding pattern of h10 hemagglutinin from avian and human isolates showed that both interact weakly with humanlike receptors and maintain strong affinity for avianlike receptors. For influenza viruses, pyrosequencing has been successfully applied to the highthroughput detection of resistance markers in genes encoding the drugtargeted m2 protein and neuraminidase. Structure and receptor binding preferences of recombinant. Therefore, ha is responsible for binding influenza virus to sialic acid on the. The frequencies of aminoacid residues were calculated for ha1 positions 104, 107, 109, and 115 and ha2 positions 73, 69, and 76 in h3 numbering. Plays a major role in the determination of host range restriction and virulence. Subtypespecific structural constraints in the evolution of influenza a virus hemagglutinin genes.
Immunodominance of antigenic site b in the hemagglutinin of. This study describes the epidemiology of influenza types a and b, and molecular characteristics of surface glycoproteins hemagglutinin ha and neuraminidase na of influenza a subtypes. Af2060 or ur060455, possibly due to the tremendous number sequenced nowadays. Nov 12, 2014 the equivalent residue numbering for these mutations in ha are listed in table 2 for those subtypes which circulate in humans h1, h3 or from which zoonoses frequently occur h5, h7, h9. The 2009 pandemic h1n1 d222g hemagglutinin mutation alters. A ribbons diagram of the trimers of h1, h3, h7 and h9 has. Influenza virus ha subtype numbering conversion tool and the. Influenza hemagglutinin h3 serotype was the first glycoprotein structure to be solved at atomic resolution, by ian wilson, john skehel and don wiley in 1981. Pdf phylogenetically important regions of the influenza a. The indicated amino acid numbers are according to the h3 numbering. For influenza hemagglutinin h3, there exists a list of canonical.
The ha of h7 strains contain many amino acid insertions and deletions indels relative to viruses from the other subtypes. Hemagglutinin, any of a group of naturally occurring glycoproteins that cause red blood cells erythrocytes to agglutinate, or clump together. It is a spikeshaped protein that extends from the surface of the virus. In the active form, shown here from pdb entry 1ruz, hemagglutinin is composed of two different types of chains, shown in blue and orange. Structure and classification of influenza virus hemagglutinins ha. The first three hemagglutinins, h1, h2, and h3, are found in human influenza viruses. A mosaic hemagglutininbased influenza virus vaccine. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Note that agglutination is one of three steps in the more complex process of coagulation. Kumar s, maurya vk, tiwari s, banerjee ak, saxena sk, et al. Characterization of highly pathogenic avian influenza virus a. Analysis of influenza hemagglutinin from awsn1933h1n1. Jun 21, 20 currently, there is anxiety that the avian h5n1 influenza virus will reassort with the highly transmissible and epidemic h1n1 subtype to trigger a virulent human pandemic.
Conversion sequence numbering scheme select one or more from the picklist to convert the existing position numbers to different subtype numbering schemes. Comparison of amino acid position 4 and 227 h3 numbering in h5 hemagglutinin ha. Transmission of hemagglutinin d222g mutant strain of. In strains from the h3 subtype, these are gln226leu and gly228ser whereas. The influenza virus hemagglutinin head evolves faster than the stalk domain. Detection of hemagglutinin variants of the pandemic influenza. Monomers 2 and 3 are in silver and gold, respectively, and the featured monomer is coloured according to its individual subdomains. The number of isolation can be a simple number, but sometimes it goes beyond. Sequence alignment tools unreliable for crosssubtype. Group 1 ha and h3 and h7 as examples of group 2 ha 11. A trimerization domain sequence has been introduced into the cterminal of ha to stabilize the formation of trimer ha. However, these measurements have suffered from substantial. Structural differences among hemagglutinins of influenza a virus. Molecular basis of the structure and function of h1 hemagglutinin of.
Ha hemagglutinin precursor influenza a virus strain a. The collaboration between the skehel and wiley labs provided great insight into hemagglutinin function, and it remains the prototype for understanding receptor recognition, antigenic variation, and the extraordinary conformational. The centers for disease control and prevention estimates that annually, seasonal influenza viruses can infect up to 20% of the human population. In the first step of infection, ha in the neutral ph conformation binds to sialic acid. There are 16 different hemagglutinin subtypes and 9 different neuraminidase subtypes, and theyre what the numbers after the letters refer to. Human influenza a virus hemagglutinin glycan evolution. Hemagglutinin ha is a transmembrane protein of the influenza a virus and a. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. Hemagglutinin is a class i fusion protein, having multifunctional activity as both an attachment factor and membrane fusion protein. Pdf comparative analysis of hemagglutinin of 20 h3n2. Mechanism of a decrease in potency for the recombinant. However, its production has proven extremely difficult. H1 and h7 influenza haemagglutinin structures extend a. The influenza virus hemagglutinin head evolves faster than.
Locations of phylogenetically informative sites in hemagglutinin. The shift in the receptorbinding specificity of avian influenza virus is critical for the jump from avian to human hosts. The rcsb pdb also provides a variety of tools and resources. Geometric constraints dominate the antigenic evolution of.
The influenza virus hemagglutinin head evolves faster than the stalk. Hemagglutinin definition of hemagglutinin by medical dictionary. Ha is synthesized as a precursor and is subsequently cleaved to form a disulfidelinked complex consisting of ha1, thereceptorbindingsubunit,andha2,thesubunitthatmediates membrane fusion 1. Is there a rational reason for using such a numbering system, or is this simply an artefact of history.
The notion that the avian ha is associated with preferential specificity for receptors with siaalpha2,3gal glycosidic linkage over those with siaalpha2,6gal linkage is not all consistent with the. The subtype refers to the aforementioned hana subtype. Among the bestcharacterized hemagglutinins are those that occur as surface antigens foreign proteins that stimulate the production of antibodies on viruses in the family. Organization and regulation within 4dnucleome nih program. Hemagglutinin receptor binding of a human isolate of. Igm, igg, and iga antibody responses to ah1n1pdm09 hemagglutinin ha following ah1n1pdm09 virus infection were analyzed to understand antibody isotype responses.
This comprised replacing the ha head region ha1 residues 43 to 3, h3 numbering with a gsg loop, replacing the ha2 interhelical region residues 60 to 92 with a 6residue glycinerich loop, including two repacking substitutions in the ha2 hydrophobic core replacing k with m at position 103 k103m and e with l at position 51 e51l, and. Jul 11, 2018 the influenza virus hemagglutinin head evolves faster than the stalk domain. Influenza a subtypes and the species affected seasonal. A pandemic h1n1 2009 virus strain carrying the d222g mutation was identified in a severely ill man and was transmitted to a household contact. The sitewise numbering for the h3 hemagglutinin protein reflects the numbering of the mature protein. Thus, for protein numbering purposes, site number 1 is actually the 17th codon in fulllength gene numbering. Data availability complementary research materials and software sharing. Hensley1,2, 1wistar institute, philadelphia, pa 19104, usa 2department of microbiology, perelman school of medicine, university of pennsylvania, philadelphia, pa 19104, usa. The hemagglutinin structure of an avian h1n1 influenza a. Recombinant influenza viruses expressing h3 ha with mutated antigenic sites. Hemagglutinin is one of the reasons that influenza virus is so effective. Hemagglutinin definition and meaning collins english dictionary.
Based on receptorbinding analysis and structural studies, song et al. The file contains commaseparated lines with the first entry giving the sequential number and the second giving the h3 number. There are only three known influenza a subtypes h1, h2, and h3 circulating among humans. Phylogenetically important regions of the influenza a h1. A recommended numbering scheme for influenza a ha subtypes. A representative example of each hemagglutinin subtype was chosen and aligned with lasergene software using the clustal method dnastar, madison, wi. We show that these measurements have utility for distinguishing among viral strains that do and do. For amino acids close to the receptor binding site, such as the aforementioned mutations, the h7 numbering differs from h3 numbering by nine residues gln217 and gly219. Burke and smiths numbering scheme uses analysis of known ha structures to identify amino acids that are structurally and functionally equivalent across all ha subtypes, using a numbering system based on the mature ha sequence.
The total number of cys residues per monomer of rha h3 is 17. Glycosylations in the globular head of the hemagglutinin. Glycosylated recombinant viral protein purified from 293 cell culture. The structure of hemagglutinin l226q mutant h3 numbering from a avianorigin h7n9 influenza. Jun 16, 2014 what exactly is the h3 numbering system. The novel influenza ah1n1pdm09 virus caused an influenza pandemic in 2009.
The name hemagglutinin comes from the proteins ability to cause red blood cells erythrocytes to clump together agglutinate in vitro. Binds to sialic acidcontaining receptors on the cell surface, bringing about the attachment of the virus particle to the cell. Prediction of nglycosylation potential of influenza virus. Based on the serological reactivity of influenza a virus surface glycoproteins, hemagglutinin ha and neuraminidase na, 18 ha h1 to h18 and 11 na n1 to n11 variants have been identified in aquatic birds and bats 1, 3. Molecular basis of the structure and function of h1. Over 95% are trimeric fraction collected from column chromatography.
The motivation for this script is that in cloning applications it is often most convenient to number ha sequentially starting with 1 at the first residue. In strains from the h3 subtype, these are gln226leu and gly228ser. In molecular biology, hemagglutinin or haemagglutinin british english. Immunodominance of antigenic site b in the hemagglutinin of the current h3n2 influenza virus in humans and mice article pdf available in journal of virology 9220. Nmr structures of fusion peptide from influenza hemagglutinin h3 subtype and its mutants overview the structures of the influenza hemagglutinin h3 hafp23 peptide and its mutants, g1s and g1v, in dodecylphosphatidyl choline micelles were studied by heteronuclear nmr spectroscopy to study the role of its amino acids in the. Influenza research database ha subtype numbering conversion. The parsimony trees were then compared with randomly generated trees to.
Jul 19, 2019 rescue and characterization of recombinant influenza viruses expressing mosaic hemagglutinin ha proteins. An analysis of nterminal cleavage sites for thirteen subtypes of influenza a hemagglutinin ha sequences, has previously been described by nobusawa and colleagues. Geometric constraints dominate the antigenic evolution of influenza. Influenza genes evolve mostly via point mutations, and so knowing the effect of every aminoacid mutation provides information about evolutionary paths available to the virus. Positions 145 and 193 h3 numbering, which in h3 hemagglutinin belong to. The hemagglutinin ha protein is the major target of protective antibody responses induced by viral infection and by vaccination with both inactivated and liveattenuated flu vaccines, but knowledge about the optimal designs of protective ha antigens from different flu serotypes is still limited. Epidemiological and genetic characterization of ph1n1 and. The isolated virus reacted fully with an antiserum against the pandemic vaccine strain. It is responsible for binding the virus to the cell that is being infected.
The globular domain consists of ha1 residues 116261 folded into a jellyroll motif of eight stranded antiparallel. We investigated the impact of this mutation in vitro and in animal models using recombinant phlnl viruses. The single d222g substitution in the ha protein of the 1918 pandemic h1n1 virus resulted in a shift in receptorbinding specificity. Subtypespecific structural constraints in the evolution of influenza a. Mechanism of a decrease in potency for the recombinant influenza a virus hemagglutinin h3 antigen during storage. Immunodominance of antigenic site b in the hemagglutinin. The structure of hemagglutinin l226q mutant h3 numbering from a avianorigin h7n9 influenza virus aanhui120 in complex with human receptor analog 6slnln. Accurate measurement of the effects of all aminoacid.
As it turns out, the numbering system is really an artefact of history. These could avoid the need for annual vaccinations and reduce pandemic threats, and the stem subdomain of the trimeric ha ectodomain would be an ideal antigen. Among the bestcharacterized hemagglutinins are those that occur as. The last, h16, was discovered only recently on influenza a viruses isolated from blackheaded gulls from sweden and norway 5. Sites are in h3 numbering, with the signal peptide in negative numbers, ha1 in plain numbers, and ha2 denoted with ha2. Production and stabilization of the trimeric influenza. A parsimony approach was used to construct phylogenetic trees of the h1, h2 and h3 influenza hemagglutinin subtypes. The shanghai virus was one of the first isolated in humans that binds avian receptor glycans with high affinity. Oct 11, 20 structural studies of two different h7n9 influenza viruses isolated from humansashanghai120 and aanhui120which have different amino acid sequences in the receptor binding site, provide data indicating that the virus is in transition with respect to host adaptation. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. Hemagglutinin ha proteins from h1 and h3 serotypes of.
Influenza surveillance is necessary for detection of emerging variants of epidemiologic and clinical significance. Igm, igg, and iga antibody responses to influenza ah1n1. The equivalent residue numbering for these mutations in ha are listed in table 2 for those subtypes which circulate in humans h1, h3 or from which zoonoses frequently occur h5, h7, h9. Influenza virus hemagglutinin ha contains antigenic sites. Thus, using h3 numbering scheme, the presence of glutamic acid e at the. Structures and receptor binding of hemagglutinins from humaninfecting h7n9 influenza viruses. Glycan addition can cause large antigenic changes but is limited by fitness costs to viral replication. A phylogenybased global nomenclature system and automated. Concerning equine h3, it sorted like avian h3 at both i 0 mm and i 150 mm. Deep mutational scanning of hemagglutinin helps predict. Structures and receptor binding of hemagglutinins from human. This attachment induces virion internalization either through clathrindependent endocytosis or through clathrin and caveolinindependent pathway. Numbering for sh1n1 strains containing a deletion outside the receptor binding. Effective antibody responses provide crucial immunity against influenza virus infection.
In this paper, we extend these considerations by comparing the structures of the h3, h5 and h9 has with that of an h7 ha from an avian influenza virus, aturkeyitaly02, which is a representative of the fourth clade. Amino acid equivalence across ha subtypes difficult to determine. Here we experimentally measure the effects of all amino acid mutations to the hemagglutinin protein from a human h3n2 influenza strain on viral growth in cell culture. The sitewise numbering for the h3 hemagglutinin protein reflects the numbering of the. Comparative structural analysis of haemagglutinin proteins from. Influenza hemagglutinin ha or haemagglutinin p british english is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity hemagglutinin is a class i fusion protein, having multifunctional activity as both an attachment factor and membrane fusion protein. In a number of ha segments from human h3n2 strains. In this study, we expanded the utility of this assay to the detection of multiple receptor binding variants of the hemagglutinin protein of influenza viruses directly in clinical specimens. A leucine residue at position 4 was deleted in highly pathogenic avian influenza virus ah5n6 isolated in japan during november 2016, compared with the closest relative afelineguangdong12015 h5n6. An airborne transmissible avian influenza h5 hemagglutinin. Three cases of influenza ah10n8 virus infection in humans have been reported. Residues that were mutated are indicated in color code.
We and others have combined highthroughput mutagenesis with deep sequencing to estimate the effects of large numbers of mutations to influenza genes. Human antibodybased immunity to influenza a virus is limited by antigenic drift resulting from amino acid substitutions in the hemagglutinin ha head domain. Here, we report that glycans are added to h1 and h3 has at discrete 5to7year intervals, until they reach a functional glycan. The interaction between hemagglutinin ha and receptors is a kernel in the study of evolution and host adaptation of h1n1 influenza a viruses. The structure of hemagglutinin l226q mutant h3 numbering from a avianorigin h7n9 influenza virus aanhui120 in complex with avian receptor analog 3slnln as a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Therefore, ha is responsible for binding influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes, 1 causing as a result the internalization of. Sites are in h3 numbering, with the signal peptide in neg. Table 2 equivalent amino acid numbering for subtypes currently circulating in humans or have pandemic potential. The d222g hi numbering hemagglutinin ha mutation within the receptorbinding site was detected with higher frequencies in severe cases of 2009 pandemic h ini ph ini infections. Jan 07, 2014 the discovery of neutralizing antibodies that block influenza infection by binding to the hemagglutinin ha stem domain raised the hope for broadly protective vaccines. To answer this question, i did a bit of digging around on the history of the h3 numbering system. Identification of hemagglutinin residues responsible for.
A v186i h3 numbering substitution in the receptorbinding site of the hemagglutinin ha molecule is responsible for the alteration of the dualreceptorbinding tropism. There are at least 16 different hemagglutinin ha antigens. The virus evolved from low pathogenic to highly pathogenic in wave 5, 2017, while the prevalence of host receptorbinding tropism in humaninfecting viruses maintained dualreceptorbinding property with preference f. Oct 01, 2011 amino acid residue 222 h1 numbering or 225 in h3 numbering, which is located in the influenza receptorbinding site, has been shown to be an important determinant of receptorbinding specificity. Mutagenesisstudiesoftheh5influenzahemagglutininstem. New hemagglutinin dualreceptorbinding pattern of a human. Acid stability of the hemagglutinin protein regulates h5n1. Only mild illness developed in the contact, despite his obesity and diabetes. Therefore, such viruses are classified based on haemagglutinin and. Hemagglutinin ha or haemagglutinin be is an antigenic glycoprotein found on the surface of the influenza viruses as well as many other bacteria and viruses.
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