A cross-clade H5N1 influenza A virus neutralizing monoclonal antibody binds to a novel epitope within the vestigial esterase domain of hemagglutinin

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A cross-clade H5N1 influenza A virus neutralizing monoclonal antibody binds to a novel epitope within the vestigial esterase domain of hemagglutinin
Title:
A cross-clade H5N1 influenza A virus neutralizing monoclonal antibody binds to a novel epitope within the vestigial esterase domain of hemagglutinin
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Antiviral Research
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Publication Date:
11 August 2017
Citation:
Subha Sankar Paul, Chee-Keng Mok, Tze-Minn Mak, Oi-Wing Ng, James Odame Aboagye, Teddy John Wohlbold, Florian Krammer, Yee-Joo Tan, A cross-clade H5N1 influenza A virus neutralizing monoclonal antibody binds to a novel epitope within the vestigial esterase domain of hemagglutinin, Antiviral Research, Volume 144, 2017, Pages 299-310, ISSN 0166-3542, https://doi.org/10.1016/j.antiviral.2017.06.012. (http://www.sciencedirect.com/science/article/pii/S0166354217300426) Abstract: The sporadic outbreaks of highly pathogenic H5N1 avian influenza virus have raised public health concerns. Monoclonal antibodies (MAbs) against hemagglutinin (HA) have been increasingly used successfully for therapeutic purposes. Previously, MAb 9F4, generated against clade 1 H5N1 HA, was observed to have cross-clade neutralizing efficacy and inhibited viral entry by preventing the pH-mediated conformational change of HA. Furthermore, mouse-human chimeric MAb 9F4 was found to retain high degrees of neutralizing activity. In this study, through escape mutant generation and in-silico prediction, it was revealed that MAb 9F4 binds to a novel epitope in the vestigial esterase sub-domain of HA comprising at least three non-continuous amino acid residues, arginine (R) at position 62, tryptophan (W) at position 69 and phenylalanine (F) at position 79, which interacted with MAb 9F4 in a conformation-dependent manner. Binding and neutralization studies suggested that R62 is the critical residue for MAb 9F4 binding whereas W69 and F79 seem to cooperate with R62 to stabilize the epitope. Mutation of either R62 or W69 did not affect replicative fitness of the virus in vitro. Interestingly, MAb 9F4 retained neutralizing efficacy against a clade 2.3.2.1a H5N1 virus consisting of an arginine to lysine substitution at position 62 in HA. Keywords: Influenza H5N1; Neutralizing monoclonal antibody; Epitope mapping; Hemagglutinin
Abstract:
The sporadic outbreaks of highly pathogenic H5N1 avian influenza virus have raised public health concerns. Monoclonal antibodies (MAbs) against hemagglutinin (HA) have been increasingly used successfully for therapeutic purposes. Previously, MAb 9F4, generated against clade 1 H5N1 HA, was observed to have cross-clade neutralizing efficacy and inhibited viral entry by preventing the pH-mediated conformational change of HA. Furthermore, mouse-human chimeric MAb 9F4 was found to retain high degrees of neutralizing activity. In this study, through escape mutant generation and in-silico prediction, it was revealed that MAb 9F4 binds to a novel epitope in the vestigial esterase sub-domain of HA comprising at least three non-continuous amino acid residues, arginine (R) at position 62, tryptophan (W) at position 69 and phenylalanine (F) at position 79, which interacted with MAb 9F4 in a conformation-dependent manner. Binding and neutralization studies suggested that R62 is the critical residue for MAb 9F4 binding whereas W69 and F79 seem to cooperate with R62 to stabilize the epitope. Mutation of either R62 or W69 did not affect replicative fitness of the virus in vitro. Interestingly, MAb 9F4 retained neutralizing efficacy against a clade 2.3.2.1a H5N1 virus consisting of an arginine to lysine substitution at position 62 in HA.
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http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
This work was supported by grants from the Ministry of Education (MOE) of Singapore [AcRF Tier 2, grant no. MOE2012-T2-1-152] and the Yong Loo Lin School of Medicine BSL-3 Core Facility and National Medical Research Council, Centre Grant MINE, Research Core no.4 (NMRC/CG/013/2013).
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ISSN:
0166-3542
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