Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus

Lee, Peter S.; Ohshima, Nobuharu; Stanfield, Robyn L.; Yu, Wenli; Iba, Yoshitaka; Okuno, Yoshinobu; Kurosawa, Yoshikazu; Wilson, Ian A.

doi:10.1038/ncomms4614

Cited by 183 publications

(219 citation statements)

References 63 publications

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“…Antibodies that possess hemagglutination-inhibiting (HAI) activity elicited against the globular domain during natural infection or vaccination is widely accepted as a correlate of protection against influenza (5,6). However, due to the high mutability (antigenic drift) of the globular head region, HAI-active antibodies typically neutralize only closely related strains, although recent reports have shown that the HA receptor binding site can be more broadly recognized (7)(8)(9)(10)(11)(12)(13). In contrast, a smaller proportion of the antibodies elicited is directed against the membrane proximal stalk region of the HA.…”

mentioning

confidence: 99%

Characterization of a Broadly Neutralizing Monoclonal Antibody That Targets the Fusion Domain of Group 2 Influenza A Virus Hemagglutinin

Tan

Lee

Hoffman

et al. 2014

J Virol

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112

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Due to continuous changes to its antigenic regions, influenza viruses can evade immune detection and cause a significant amount of morbidity and mortality around the world. Influenza vaccinations can protect against disease but must be annually reformulated to match the current circulating strains. In the development of a broad-spectrum influenza vaccine, the elucidation of conserved epitopes is paramount. To this end, we designed an immunization strategy in mice to boost the humoral response against conserved regions of the hemagglutinin (HA) glycoprotein. Of note, generation and identification of broadly neutralizing antibodies that target group 2 HAs are rare and thus far have yielded only a few monoclonal antibodies (MAbs). Here, we demonstrate that mouse MAb 9H10 has broad and potent in vitro neutralizing activity against H3 and H10 group 2 influenza A subtypes. In the mouse model, MAb 9H10 protects mice against two divergent mouse-adapted H3N2 strains, in both pre-and postexposure administration regimens. In vitro and cell-free assays suggest that MAb 9H10 inhibits viral replication by blocking HA-dependent fusion of the viral and endosomal membranes early in the replication cycle and by disrupting viral particle egress in the late stage of infection. Interestingly, electron microscopy reconstructions of MAb 9H10 bound to the HA reveal that it binds a similar binding footprint to MAbs CR8020 and CR8043. IMPORTANCEThe influenza hemagglutinin is the major antigenic target of the humoral immune response. However, due to continuous antigenic changes that occur on the surface of this glycoprotein, influenza viruses can escape the immune system and cause significant disease to the host. Toward the development of broad-spectrum therapeutics and vaccines against influenza virus, elucidation of conserved regions of influenza viruses is crucial. Thus, defining these types of epitopes through the generation and characterization of broadly neutralizing monoclonal antibodies (MAbs) can greatly assist others in highlighting conserved regions of hemagglutinin. Here, we demonstrate that MAb 9H10 that targets the hemagglutinin stalk has broadly neutralizing activity against group 2 influenza A viruses in vitro and in vivo.

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confidence: 99%

Characterization of a Broadly Neutralizing Monoclonal Antibody That Targets the Fusion Domain of Group 2 Influenza A Virus Hemagglutinin

Tan

Lee

Hoffman

et al. 2014

J Virol

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112

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“…Because the H5.3 CDRH3 inserts into the RBS, we compared the H5.3-H5hd complexes with the structure of the avian receptor analog (α2,3-SLN; 3′-sialyl-N-acetyllactosamine) bound to A/Vietnam/1194/2004 H5 (PDB ID code 4BGY) (18) and to influenza HA-antibody complexes that similarly project CDRH3 into the RBS (PDB ID codes 3SM5, 4HKX, 4M5Z, 4O5I, 2VIR, and 1KEN) (33)(34)(35)(36)(37)(38) (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Winarski

Thornburg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. Here, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility. structural biology | immunity | antigen recognition | affinity maturation | influenza I nfluenza remains a major public health concern because seasonal influenza infects 600 million to 1.1 billion people annually, resulting in 3-5 million cases of severe disease, and 250,000-500,000 deaths (1). By comparison, the four influenza pandemics of the 20th century, caused by novel influenza strains infecting the immunologically naive human population, resulted in 50-100 million deaths (1-4). Influenza A immunity is principally mediated by the antibody response to the viral glycoprotein, hemagglutinin (HA) (5). HA is expressed as a preprotein, HA0, assembled as a trimer on the viral envelope, and cleaved by host proteases into HA1 and HA2. HA1 is a largely globular domain responsible for receptor binding, and HA2 is a rod-shaped helical bundle responsible for membrane fusion (Fig. 1A) (5). There are 18 genetically distinct subtypes of influenza A HA (H1-H18), of which only H1 and H3 currently circulate among humans (1,(6)(7)(8)(9).Despite the widespread presence of H5N1 influenza viruses in wild birds, the virus is not currently transmissible within the human population. Human-to-human transmission is inefficient and is partially restricted by the receptor specificity of the virus; human-type HAs preferentially recognize α2,6-linked sialic acid whereas avian-type HAs prefer α2,3-linked sialic acid (1, 10-12). However, there have been >600 human cases of H5N1 infection since 2004, resulting from the direct transmission of the virus from birds to humans, associated with an ∼60% mortality rate. There is the potential for a significant pandemic if H5 viruses develop the ability to spread efficiently b...

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“…One of the key recognition elements is mimicry of the interactions of the endogenous sialic acid receptor, where an Asp residue in HCDR3 corresponds to the carboxylate of sialic acid. This feature has also been found in (Hong et al, 2013;Lee et al, 2014). However, the unmutated common ancestor (UCA) and the intermediate (I-2) precursor antibodies in the CH65-CH67 lineage have significantly weaker affinity for the H1 HAs (Schmidt et al, 2013).…”

Section: Introductionmentioning

confidence: 82%

Structure of the apo anti-influenza CH65 Fab

2015

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Influenza viruses remain a persistent challenge to human health owing to their inherent ability to evade the immune response by antigenic drift. However, the discovery of broadly neutralizing antibodies (bnAbs) against divergent viruses has sparked renewed interest in a universal influenza vaccine and novel therapeutic opportunities. Here, a crystal structure at 1.70 Å resolution is presented of the Fab of the human antibody CH65, which has broad neutralizing activity against a range of seasonal H1 isolates. Previous studies proposed that affinity maturation of this antibody lineage pre-organizes the complementaritydetermining region (CDR) loops into an energetically favorable HA-bound conformation. Indeed, from the structural comparisons of free and HA-bound CH65 presented here, the CDR loops, and in particular the heavy-chain CDR3, adopt the same conformations in the free and bound forms. Thus, these findings support the notion that affinity maturation of the CH65 lineage favorably preconfigures the CDR loops for high-affinity binding to influenza hemagglutinin.

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Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus

Cited by 183 publications

References 63 publications

Characterization of a Broadly Neutralizing Monoclonal Antibody That Targets the Fusion Domain of Group 2 Influenza A Virus Hemagglutinin

Characterization of a Broadly Neutralizing Monoclonal Antibody That Targets the Fusion Domain of Group 2 Influenza A Virus Hemagglutinin

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Structure of the apo anti-influenza CH65 Fab

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