Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues that Are Prone to Escape due to Host Selection Pressure

Tharakaraman, Kannan; Subramanian, Vidya; Cain, David; Sasisekharan, V.; Sasisekharan, Ram

doi:10.1016/j.chom.2014.04.009

Cited by 61 publications

(49 citation statements)

References 33 publications

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“…Unfortunately, CR8020 has been less effective against the recent H7N9 virus 27 . In this study, we generated a combinatorial library with blood from patients recovering from H7N9 infection and screened this library for neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus

et al. 2015

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The recently identified avian-originated influenza H7N9 virus causes severe pulmonary disease and may lead to death in humans. Currently, treatment options for the prevention and control of fatal H7N9 infections in humans remain limited. Here we characterize two human monoclonal antibodies (HuMAbs), HNIgGA6 and HNIgGB5, by screening a Fab antibody phage library derived from patients who recovered from H7N9 infection. Both antibodies exhibit high neutralizing activity against H7N9 virus in cells. Two amino acids in the receptorbinding site, 186V and 226L, are crucial for the binding of these two HuMAbs to viral haemagglutinin antigens. Prophylaxis with HNIgGA6 and HNIgGB5 confers significant immunity against H7N9 virus in a mouse model and significantly reduces the pulmonary virus titre. When administered post infection, therapeutic doses of the HuMAbs also provide robust protection against lethality. These antibodies might represent a potential alternative or adjunct to H7N9 pandemic interventions.

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Section: Discussionmentioning

confidence: 99%

Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus

et al. 2015

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“…One mutant completely abolished binding of antibody 39.29 to the HA stem, whereas the other two mutants escape by increasing fusion efficiency [118]. Other examples include escape mutants against stem-binding bnAbs C179 [103], CR8020 [107, 119], CR6261 [108], and CR8043 [109]. Although some escape mutants against stem-binding bnAbs have been shown to reduce viral replication fitness [106, 118], compensatory mutations may exist.…”

Section: Functionally Conserved Region 2: Membrane Fusionmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

142

174

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Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin glycoprotein (HA), which is the major antigen on the surface of the virus. The HA is comprised of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino-acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site (RBS) and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines as well as novel therapeutics.

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“…It has been demonstrated that those conserved regions in structural proteins have an important role in viral fitness and might be targets of broadly neutralising antibodies in viruses such as HIV and Influenza A virus. For instance, although the majority of the protective immune response against influenza virus is provided by antibodies against the head of haemagglutinin (HA), new classes of multi-neutralising antibodies have been isolated that target the highly conserved HA stalk region121314151617. Antibodies with similar properties have also been found that target functionally conserved regions of HIV glycoprotein 1201819202122.…”

mentioning

confidence: 99%

Genome-wide analyses reveal a highly conserved Dengue virus envelope peptide which is critical for virus viability and antigenic in humans

Fleith

Lobo

Santos

et al. 2016

Sci Rep

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Targeting regions of proteins that show a high degree of structural conservation has been proposed as a method of developing immunotherapies and vaccines that may bypass the wide genetic variability of RNA viruses. Despite several attempts, a vaccine that protects evenly against the four circulating Dengue virus (DV) serotypes remains elusive. To find critical conserved amino acids in dengue viruses, 120 complete genomes of each serotype were selected at random and used to calculate conservation scores for nucleotide and amino acid sequences. The identified peptide sequences were analysed for their structural conservation and localisation using crystallographic data. The longest, surface exposed, highly conserved peptide of Envelope protein was found to correspond to amino acid residues 250 to 270. Mutation of this peptide in DV1 was lethal, since no replication of the mutant virus was detected in human cells. Antibodies against this peptide were detected in DV naturally infected patients indicating its potential antigenicity. Hence, this study has identified a highly conserved, critical peptide in DV that is a target of antibodies in infected humans.

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Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues that Are Prone to Escape due to Host Selection Pressure

Cited by 61 publications

References 33 publications

Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus

Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Genome-wide analyses reveal a highly conserved Dengue virus envelope peptide which is critical for virus viability and antigenic in humans

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