A Unique and Conserved Neutralization Epitope in H5N1 Influenza Viruses Identified by an Antibody against the A/Goose/Guangdong/1/96 Hemagglutinin

Zhu, Xueyong; Guo, Yaqiong; Jiang, Tao; Wang, Yadi; Chan, Kwok‐Hung; Li, Xiaofeng; Yu, Wenli; McBride, Ryan; Paulson, James C.; Yuen, Kwok‐Yung; Qin, Cheng‐Feng; Che, Xin; Wilson, Ian A.

doi:10.1128/jvi.01577-13

Cited by 54 publications

(56 citation statements)

References 65 publications

(82 reference statements)

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“…In addition, binding of F005-126 to a vestigial esterase (VE) subdomain, in which site R is located, may be related to prevention of conformational changes in HA. A mouse Ab, H5M9, recognizing an epitope including the VE domain in H5 HA prevents the conformational changes in HA, although the mechanisms for prevention remain unknown (59). In the case of H2 HA, low pH induces large deformation of the VE domain, and the domain serves as the relative flexible linker between the rigid receptor-binding domain and F= fusion subdomain (56).…”

mentioning

confidence: 99%

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

Iba

Fujii

Ohshima

et al. 2014

J Virol

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Neutralizing antibodies that target the hemagglutinin of influenza virus either inhibit binding of hemagglutinin to cellular receptors or prevent the low-pH-induced conformational change in hemagglutinin required for membrane fusion. In general, the former type of antibody binds to the globular head formed by HA1 and has narrow strain specificity, while the latter type binds to the stem mainly formed by HA2 and has broad strain specificity. In the present study, we analyzed the epitope and function of a broadly neutralizing human antibody against H3N2 viruses, F005-126. The crystal structure of F005-126 Fab in complex with hemagglutinin revealed that the antibody binds to the globular head, spans a cleft formed by two hemagglutinin monomers in a hemagglutinin trimer, and cross-links them. It recognizes two peptide portions (sites L and R) and a glycan linked to asparagine at residue 285 using three complementarity-determining regions and framework 3 in the heavy chain. Binding of the antibody to sites L (residues 171 to 173, 239, and 240) and R (residues 91, 92, 270 to 273, 284, and 285) is mediated mainly by van der Waals contacts with the main chains of the peptides in these sites and secondarily by hydrogen bonds with a few side chains of conserved sequences in HA1. Furthermore, the glycan recognized by F005-126 is conserved among H3N2 viruses. F005-126 has the ability to prevent low-pH-induced conformational changes in hemagglutinin. The newly identified conserved epitope, including the glycan, should be immunogenic in humans and may induce production of broadly neutralizing antibodies against H3 viruses. IMPORTANCEAntibodies play an important role in protection against influenza virus, and hemagglutinin is the major target for virus neutralizing antibodies. It has long been believed that all effective neutralizing antibodies bind to the surrounding regions of the sialic acid-binding pocket and inhibit the binding of hemagglutinin to the cellular receptor. Since mutations are readily introduced into such epitopes, this type of antibody shows narrow strain specificity. Recently, however, broadly neutralizing antibodies have been isolated. Most of these bind either to conserved sites in the stem region or to the sialic acid-binding pocket itself. In the present study, we identified a new neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against H3N2. This epitope may be useful for design of vaccines.

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confidence: 99%

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

Iba

Fujii

Ohshima

et al. 2014

J Virol

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“…3B). However, this epitope was different from the reported epitope of mouse mAb H5M9 [14] and is present outside the VE subdomain. The reason for this difference has not been established.…”

Section: Generation Of Neutralising Mabs Binding To the Ve Subdomainmentioning

confidence: 54%

“…Previously, two mAbs H5M9 [14] and 4F5 [15], were reported to interact with amino acid residues close to 9F4's binding site. H5M9 was produced by immunising mice with HA protein of A/Goose/Guangdong/1/96 (H5N1).…”

Section: Generation Of Neutralising Mabs Binding To the Ve Subdomainmentioning

confidence: 99%

“…Interestingly, several mAbs in this class have been documented to bind to the vestigial esterase (VE) subdomain of HA of the H5N1 subtype and they have been shown to bind to multiple clades of H5N1 viruses [11][12][13][14][15]. However, they typically do not bind to other subtypes of IAV which suggests that the VE subdomain is conserved within a subtype but diverse among subtypes.…”

Section: Introductionmentioning

confidence: 99%

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The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Zheng

Paul

et al. 2018

Preprint

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Initial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and micro-neutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA) which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain specific. This led to the emphasis on stalk targeting antibodies which are able to bind a broad range of viral targets that span across different influenza subtypes.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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“…In addition, Abs against the globular head with different degrees of cross-reactivity have also been isolated (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Many of these Abs are virus strain specific and recognize epitopes located in the receptor binding site (RBS), but some Abs recognize conserved epitopes within or outside the RBS of diverse strains of different subtypes (17)(18)(19) or within a HA subtype (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The antibody repertoire against epitopes located in the head is more diverse than those Abs targeting epitopes in the stem (31).…”

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confidence: 99%

Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

Wang

Ren

Jiang

et al. 2017

J Virol

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Recent studies have shown that Fc-Fc␥ receptor (Fc␥R) interactions are required for in vivo protection against influenza viruses by broadly reactive antihemagglutinin (HA) stem, but not virus strain-specific, anti-receptor binding site (RBS), antibodies (Abs). Since only a few Abs recognizing epitopes in the head region but outside the RBS have been tested against single-challenge virus strains, it remains unknown whether Fc-Fc␥R interactions are required for in vivo protection by Abs recognizing epitopes outside the RBS and whether the requirement is virus strain specific or epitope specific. In the present study, we therefore investigated the requirements for in vivo protection using two pan-H5 Abs, 65C6 and 100F4. We generated chimeric Abs, 65C6/IgG2a and 100F4/IgG2a, which preferentially engage activating Fc␥Rs, and isogenic forms, 65C6/D265A and 100F4/D265A, which do not bind Fc␥R. Virus neutralizing activity, binding, antibody-dependent cellular cytotoxicity (ADCC), and in vivo protection of these Abs were compared using three H5 strains, A/Shenzhen/406H/2006 (SZ06), A/chicken/Shanxi/2/2006 (SX06), and A/chicken/Netherlands/14015526/2014 (NE14). We found that all four chimeric Abs bound and neutralized the SZ06 and NE14 strains but poorly inhibited the SX06 strain. 65C6/IgG2a and 100F4/IgG2a, but not 65C6/D265A and 100F4/D265A, mediated ADCC against target cells expressing HA derived from all three virus strains. Interestingly, both 65C6/IgG2a and 65C6/D265A demonstrated comparable protection against all three virus strains in vivo; however, 100F4/IgG2a, but not 100F4/D265A, showed in vivo protection. Thus, we conclude that Fc-Fc␥R interactions are required for in vivo protection by 100F4, but not by 65C6, and therefore, protection is not virus strain specific but epitope specific.IMPORTANCE Abs play an important role in immune protection against influenza virus infection. Fc-Fc␥R interactions are required for in vivo protection by broadly neutralizing antistem, but not by virus strain-specific, anti-receptor binding site (RBS), Abs. Whether such interactions are necessary for protection by Abs that recognize epitopes outside RBS is not fully understood. In the present study, we investigated in vivo protection mechanisms against three H5 strains by two pan-H5 Abs, 65C6 and 100F4. We show that although these two Abs have similar neutralizing, binding, and ADCC activities against all three H5 strains in vitro, they have divergent requirements for Fc-Fc␥R interactions to protect against the three H5 strains in vivo. The FcFc␥R interactions are required for in vivo protection by 100F4, but not by 65C6. Thus, we conclude that Fc-Fc␥R interactions for in vivo protection by pan-H5 Abs is not strain specific, but epitope specific.KEYWORDS influenza viruses, in vivo protection, monoclonal antibodies

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A Unique and Conserved Neutralization Epitope in H5N1 Influenza Viruses Identified by an Antibody against the A/Goose/Guangdong/1/96 Hemagglutinin

Cited by 54 publications

References 65 publications

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses

The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

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