Compensatory Hemagglutinin Mutations Alter Antigenic Properties of Influenza Viruses

Myers, Jaclyn L.; Wetzel, Katherine S.; Linderman, Susanne L.; Yang, Li; Sullivan, Colleen B.; Hensley, Scott E.

doi:10.1128/jvi.01414-13

Cited by 31 publications

(30 citation statements)

References 22 publications

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“…Antigenic changes can come at a cost of fitness, sometimes due to lower avidity to sialic acids, and substitutions outside the antigenic motif may be compensatory mutations or simply hitchhiker mutations (43,44,54,55). We selected one OH/04 mutant with large antigenic changes to assess in vivo other virus properties and found that its replication in the upper and lower respiratory tract in directly inoculated pigs was comparable to that of wt OH/04 but caused significantly lower levels of lung lesions (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus

Abente

Santos

Lewis

et al. 2016

J Virol

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Influenza A virus (IAV) of the H3 subtype is an important respiratory pathogen that affects both humans and swine. Vaccination to induce neutralizing antibodies against the surface glycoprotein hemagglutinin (HA) is the primary method used to control disease. However, due to antigenic drift, vaccine strains must be periodically updated. Six of the 7 positions previously identified in human seasonal H3 (positions 145, 155, 156, 158, 159, 189, and 193) were also indicated in swine H3 antigenic evolution. To experimentally test the effect on virus antigenicity of these 7 positions, substitutions were introduced into the HA of an isogenic swine lineage virus. We tested the antigenic effect of these introduced substitutions by using hemagglutination inhibition (HI) data with monovalent swine antisera and antigenic cartography to evaluate the antigenic phenotype of the mutant viruses. Combinations of substitutions within the antigenic motif caused significant changes in antigenicity. One virus mutant that varied at only two positions relative to the wild type had a >4-fold reduction in HI titers compared to homologous antisera. Potential changes in pathogenesis and transmission of the double mutant were evaluated in pigs. Although the double mutant had virus shedding titers and transmissibility comparable to those of the wild type, it caused a significantly lower percentage of lung lesions. Elucidating the antigenic effects of specific amino acid substitutions at these sites in swine H3 IAV has important implications for understanding IAV evolution within pigs as well as for improved vaccine development and control strategies in swine. IMPORTANCEA key component of influenza virus evolution is antigenic drift mediated by the accumulation of amino acid substitutions in the hemagglutinin (HA) protein, resulting in escape from prior immunity generated by natural infection or vaccination. Understanding which amino acid positions of the HA contribute to the ability of the virus to avoid prior immunity is important for understanding antigenic evolution and informs vaccine efficacy predictions based on the genetic sequence data from currently circulating strains. Following our previous work characterizing antigenic phenotypes of contemporary wild-type swine H3 influenza viruses, we experimentally validated that substitutions at 6 amino acid positions in the HA protein have major effects on antigenicity. An improved understanding of the antigenic diversity of swine influenza will facilitate a rational approach for selecting more effective vaccine components to control the circulation of influenza in pigs and reduce the potential for zoonotic viruses to emerge. I nfluenza A virus (IAV) of the H3 subtype is an important pathogen that infects both humans and swine. The main strategy used to prevent or reduce morbidity of IAV in humans is the implementation of vaccine programs (1). Likewise, swine producers employ commercially available and farm-specific autogenous vaccines to prevent IAV clinical disease in swine (2, 3). ...

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Section: Discussionmentioning

confidence: 99%

The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus

Abente

Santos

Lewis

et al. 2016

J Virol

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“…Models of pathogen evolu-tion can help to establish whether such approaches will completely stall adaptation of the pathogen or with what likelihood the designed fitness valleys would be crossed. Moreover, such approaches could also be used to explore alternative routes as a result of epistatic interactions that might allow deleterious mutations to occur if they are acquired in the right order (15,17,20).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the altered receptor-binding avidity and lower replication resulting from the antigenic escape mutation HA K165E in A/Puerto Rico/8/1934 (H1N1) could be compensated for by mutations in HA or the neuraminidase (NA) (15,16), and stabilizing mutations were required to occur prior to the introduction of immune-escape mutations in influenza A/H3N2 virus (17). Similarly, there are numerous examples where antiviral resistance-conferring mutations come at a fitness cost for the virus but can be compensated for by other mutations: several neuraminidase substitutions can occur and have occurred as either permissive or compensatory mutations to counteract the adverse fitness effects of the oseltamivir resistance mutation NA H275Y in influenza A/H1N1 virus (18)(19)(20), and similarly, the I222V NA mutation in influenza A/H3N2 virus partially restored the viral fitness-decreasing oseltamivir resistance mutation NA E119V (21).…”

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confidence: 99%

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Fonville

2015

J Virol

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Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCEAdaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models. The fitness landscape of a pathogen is likely to have a rugged shape and consist of multiple optima. Reductions in fitness occur when underlying combinations of genetic mutations lead to an unfit or deleterious phenotype, creating depressions in the...

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“…Why is this the case if only 1 antigenic site is antigenically important? One possible explanation is that mutations in non-immunodominant antigenic sites offset viral fitness costs associated with mutations in immunodominant antigenic sites [25,28]. An alternative explanation is that all 5 HA antigenic sites are actually antigenically relevant, but that the ferret reference sera used to create antigenic maps in these studies are not fully representative of human immunity.…”

Section: Genetic Variation Versus Antigenic Variationmentioning

confidence: 99%

Challenges of selecting seasonal influenza vaccine strains for humans with diverse pre-exposure histories

Hensley

2014

Current Opinion in Virology

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Seasonal influenza vaccine strains are routinely updated when influenza viruses acquire mutations in exposed regions of the hemagglutinin and neuraminidase glycoproteins. Ironically, although thousands of viral isolates are sequenced each year, today's influenza surveillance community places less emphasis on viral genetic information and more emphasis on classical serological assays when choosing vaccine strains. Here, I argue that these classical serological assays are oversimplified and that they fail to detect influenza mutations that facilitate escape of particular types of human antibodies. I propose that influenza vaccine strains should be updated more frequently even when classical serological assays fail to detect significant antigenic alterations.

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Compensatory Hemagglutinin Mutations Alter Antigenic Properties of Influenza Viruses

Cited by 31 publications

References 22 publications

The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus

The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Challenges of selecting seasonal influenza vaccine strains for humans with diverse pre-exposure histories

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