Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms

ABSTRACT Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which...

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Autores principales:	Abimbola O. Kolawole, Hong Q. Smith, Sophia A. Svoboda, Madeline S. Lewis, Michael B. Sherman, Gillian C. Lynch, B. Montgomery Pettitt, Thomas J. Smith, Christiane E. Wobus
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	antibody neutralization noroviruses protein structure-function Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8c3e915739ee40cdb50d1aac4ea2b75c
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spelling	oai:doaj.org-article:8c3e915739ee40cdb50d1aac4ea2b75c2021-11-15T15:22:05ZNorovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms10.1128/mSphere.00334-172379-5042https://doaj.org/article/8c3e915739ee40cdb50d1aac4ea2b75c2017-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00334-17https://doaj.org/toc/2379-5042ABSTRACT Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex. Interestingly, 2D3 binds to the top of the P domain, very close to where A6.2 binds, but the only escape mutations identified to date fall well outside the contact regions of both 2D3 and A6.2. To determine how mutations in distal residues could block antibody binding, we used molecular dynamics flexible fitting simulations of the atomic structures placed into the density map to examine the 2D3/MNV1 complex and these mutations. Our findings suggest that the escape mutant, V339I, may stabilize a salt bridge network at the P-domain dimer interface that, in an allostery-like manner, affects the conformational relaxation of the P domain and the efficiency of binding. They further highlight the unusual antigenic surface bound by MAb 2D3, one which elicits cross-reactive antibodies but which the virus is unable to alter to escape neutralization. These results may be leveraged to generate norovirus (NoV) vaccines containing broadly neutralizing antibodies. IMPORTANCE The simplest and most common way for viruses to escape antibody neutralization is by mutating residues that are essential for antibody binding. Escape mutations are strongly selected for by their effect on viral fitness, which is most often related to issues of protein folding, particle assembly, and capsid function. The studies presented here demonstrated that a broadly neutralizing antibody to mouse norovirus binds to an exposed surface but that the only escape mutants that arose were distal to the antibody binding surface. To understand this finding, we performed an in silico analysis that suggested that those escape mutations blocked antibody binding by affecting structural plasticity. This kind of antigenic region—one that gives rise to broadly neutralizing antibodies but that the virus finds difficult to escape from—is therefore ideal for vaccine development.Abimbola O. KolawoleHong Q. SmithSophia A. SvobodaMadeline S. LewisMichael B. ShermanGillian C. LynchB. Montgomery PettittThomas J. SmithChristiane E. WobusAmerican Society for Microbiologyarticleantibodyneutralizationnorovirusesprotein structure-functionMicrobiologyQR1-502ENmSphere, Vol 2, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibody neutralization noroviruses protein structure-function Microbiology QR1-502
spellingShingle	antibody neutralization noroviruses protein structure-function Microbiology QR1-502 Abimbola O. Kolawole Hong Q. Smith Sophia A. Svoboda Madeline S. Lewis Michael B. Sherman Gillian C. Lynch B. Montgomery Pettitt Thomas J. Smith Christiane E. Wobus Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
description	ABSTRACT Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex. Interestingly, 2D3 binds to the top of the P domain, very close to where A6.2 binds, but the only escape mutations identified to date fall well outside the contact regions of both 2D3 and A6.2. To determine how mutations in distal residues could block antibody binding, we used molecular dynamics flexible fitting simulations of the atomic structures placed into the density map to examine the 2D3/MNV1 complex and these mutations. Our findings suggest that the escape mutant, V339I, may stabilize a salt bridge network at the P-domain dimer interface that, in an allostery-like manner, affects the conformational relaxation of the P domain and the efficiency of binding. They further highlight the unusual antigenic surface bound by MAb 2D3, one which elicits cross-reactive antibodies but which the virus is unable to alter to escape neutralization. These results may be leveraged to generate norovirus (NoV) vaccines containing broadly neutralizing antibodies. IMPORTANCE The simplest and most common way for viruses to escape antibody neutralization is by mutating residues that are essential for antibody binding. Escape mutations are strongly selected for by their effect on viral fitness, which is most often related to issues of protein folding, particle assembly, and capsid function. The studies presented here demonstrated that a broadly neutralizing antibody to mouse norovirus binds to an exposed surface but that the only escape mutants that arose were distal to the antibody binding surface. To understand this finding, we performed an in silico analysis that suggested that those escape mutations blocked antibody binding by affecting structural plasticity. This kind of antigenic region—one that gives rise to broadly neutralizing antibodies but that the virus finds difficult to escape from—is therefore ideal for vaccine development.
format	article
author	Abimbola O. Kolawole Hong Q. Smith Sophia A. Svoboda Madeline S. Lewis Michael B. Sherman Gillian C. Lynch B. Montgomery Pettitt Thomas J. Smith Christiane E. Wobus
author_facet	Abimbola O. Kolawole Hong Q. Smith Sophia A. Svoboda Madeline S. Lewis Michael B. Sherman Gillian C. Lynch B. Montgomery Pettitt Thomas J. Smith Christiane E. Wobus
author_sort	Abimbola O. Kolawole
title	Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
title_short	Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
title_full	Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
title_fullStr	Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
title_full_unstemmed	Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms
title_sort	norovirus escape from broadly neutralizing antibodies is limited to allostery-like mechanisms
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/8c3e915739ee40cdb50d1aac4ea2b75c
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Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms

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