scholarly journals Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Juhye M Lee ◽  
Rachel Eguia ◽  
Seth J Zost ◽  
Saket Choudhary ◽  
Patrick C Wilson ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Evolution ◽  
Surface Protein ◽  
Viral Escape ◽  
Viral Neutralization ◽  
Influenza Hemagglutinin ◽  
Human Sera ◽  
Order Of Magnitude ◽  
Amino Acid Mutations ◽  
Major Surface

A longstanding question is how influenza virus evolves to escape human immunity, which is polyclonal and can target many distinct epitopes. Here, we map how all amino-acid mutations to influenza’s major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets that have been infected just once with a defined viral strain. Our results show how different single mutations help influenza virus escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.

scholarly journals Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

2019 ◽  
Author(s):  
Juhye M. Lee ◽  
Rachel Eguia ◽  
Seth J. Zost ◽  
Saket Choudhary ◽  
Patrick C. Wilson ◽  
...  
Keyword(s):  
Viral Evolution ◽  
Surface Protein ◽  
Viral Escape ◽  
Viral Neutralization ◽  
Influenza Hemagglutinin ◽  
Human Sera ◽  
Order Of Magnitude ◽  
Amino Acid Mutations ◽  
Major Surface ◽  
Polyclonal Serum

AbstractA longstanding question is how influenza evolves to escape human immunity, which is polyclonal and can target many distinct epitopes on the virus. Here we map how all amino-acid mutations to influenza’s major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations isnotpresent among ferrets, which are frequently used as a model in influenza studies. Our results show how different single mutations help influenza escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.

scholarly journals Quantifying the effects of single mutations on viral escape from broad and narrow antibodies to an H1 influenza hemagglutinin

2017 ◽  
Author(s):  
Michael B. Doud ◽  
Juhye M. Lee ◽  
Jesse D. Bloom
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Effect Sizes ◽  
Single Amino Acid ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
Influenza Hemagglutinin ◽  
Amino Acid Mutations ◽  
Do So

ABSTRACTInfluenza virus can completely escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if it was under strong pressure to do so. Here we map all single amino-acid mutations that increase resistance to broad antibodies targeting an H1 hemagglutinin. Crucially, our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody that targets residues in hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies targeting hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we have examined, breadth is an imperfect indicator of the potential for viral escape via single mutations. Broadly neutralizing antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.

scholarly journals Learning the language of viral evolution and escape

Science ◽  
2021 ◽  
Vol 371 (6526) ◽  
pp. 284-288 ◽  
Author(s):  
Brian Hie ◽  
Ellen D. Zhong ◽  
Bonnie Berger ◽  
Bryan Bryson
Keyword(s):  
Immune System ◽  
Natural Language ◽  
Vaccine Development ◽  
Sequence Data ◽  
Viral Evolution ◽  
Machine Learning Algorithms ◽  
Language Models ◽  
Viral Escape ◽  
Human Immune System ◽  
Influenza Hemagglutinin

The ability for viruses to mutate and evade the human immune system and cause infection, called viral escape, remains an obstacle to antiviral and vaccine development. Understanding the complex rules that govern escape could inform therapeutic design. We modeled viral escape with machine learning algorithms originally developed for human natural language. We identified escape mutations as those that preserve viral infectivity but cause a virus to look different to the immune system, akin to word changes that preserve a sentence’s grammaticality but change its meaning. With this approach, language models of influenza hemagglutinin, HIV-1 envelope glycoprotein (HIV Env), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike viral proteins can accurately predict structural escape patterns using sequence data alone. Our study represents a promising conceptual bridge between natural language and viral evolution.

scholarly journals Deep mutational scanning of hemagglutinin helps predict evolutionary fates of human H3N2 influenza variants

2018 ◽  
Vol 115 (35) ◽  
pp. E8276-E8285 ◽  
Author(s):  
Juhye M. Lee ◽  
John Huddleston ◽  
Michael B. Doud ◽  
Kathryn A. Hooper ◽  
Nicholas C. Wu ◽  
...  
Keyword(s):  
Cell Culture ◽  
Influenza Virus ◽  
Surface Protein ◽  
Viral Fitness ◽  
Single Amino Acid ◽  
Similar Data ◽  
Human Influenza Virus ◽  
Viral Growth ◽  
H3n2 Influenza ◽  
Major Surface

Human influenza virus rapidly accumulates mutations in its major surface protein hemagglutinin (HA). The evolutionary success of influenza virus lineages depends on how these mutations affect HA’s functionality and antigenicity. Here we experimentally measure the effects on viral growth in cell culture of all single amino acid mutations to the HA from a recent human H3N2 influenza virus strain. We show that mutations that are measured to be more favorable for viral growth are enriched in evolutionarily successful H3N2 viral lineages relative to mutations that are measured to be less favorable for viral growth. Therefore, despite the well-known caveats about cell-culture measurements of viral fitness, such measurements can still be informative for understanding evolution in nature. We also compare our measurements for H3 HA to similar data previously generated for a distantly related H1 HA and find substantial differences in which amino acids are preferred at many sites. For instance, the H3 HA has less disparity in mutational tolerance between the head and stalk domains than the H1 HA. Overall, our work suggests that experimental measurements of mutational effects can be leveraged to help understand the evolutionary fates of viral lineages in nature—but only when the measurements are made on a viral strain similar to the ones being studied in nature.

scholarly journals Learning the language of viral evolution and escape

2020 ◽  
Author(s):  
Brian Hie ◽  
Ellen Zhong ◽  
Bonnie Berger ◽  
Bryan Bryson
Keyword(s):  
Natural Language ◽  
Vaccine Development ◽  
Viral Evolution ◽  
Machine Learning Algorithms ◽  
Viral Fitness ◽  
Language Models ◽  
Viral Escape ◽  
Semantic Change ◽  
Influenza Hemagglutinin ◽  
Escape Mutants

AbstractViral mutation that escapes from human immunity remains a major obstacle to antiviral and vaccine development. While anticipating escape could aid rational therapeutic design, the complex rules governing viral escape are challenging to model. Here, we demonstrate an unprecedented ability to predict viral escape by using machine learning algorithms originally developed to model the complexity of human natural language. Our key conceptual advance is that predicting escape requires identifying mutations that preserve viral fitness, or “grammaticality,” and also induce high antigenic change, or “semantic change.” We develop viral language models for influenza hemagglutinin, HIV Env, and SARS-CoV-2 Spike that we use to construct antigenically meaningful semantic landscapes, perform completely unsupervised prediction of escape mutants, and learn structural escape patterns from sequence alone. More profoundly, we lay a promising conceptual bridge between natural language and viral evolution.One sentence summaryNeural language models of semantic change and grammaticality enable unprecedented prediction of viral escape mutations.

scholarly journals Accurate measurement of the effects of all amino-acid mutations to influenza hemagglutinin

2016 ◽  
Author(s):  
Michael B. Doud ◽  
Jesse D. Bloom
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Viral Evolution ◽  
Point Mutations ◽  
Helper Virus ◽  
Broadly Neutralizing Antibodies ◽  
Amino Acid Mutation ◽  
Influenza Hemagglutinin ◽  
Amino Acid Mutations ◽  
Evolutionary Paths

AbstractInfluenza genes evolve mostly via point mutations, and so knowing the effect of every amino-acid mutation provides information about evolutionary paths available to the virus. We previously used high-throughput mutagenesis and deep sequencing to estimate the effects of all mutations to an H1 influenza hemagglutinin on viral replication in cell culture (Thyagarajan and Bloom, 2014); however, these measurements suffered from sub-stantial noise. Here we describe advances that greatly improve the accuracy and reproducibility of our measurements. The largest improvements come from using a helper virus to reduce bottlenecks when generating viruses from plasmids. Our measurements confirm that antigenic sites on the globular head of hemagglutinin are highly tolerant of mutations. However, other regions – including stalk epitopes targeted by broadly neutralizing antibodies – have a limited capacity to evolve. The ability to accurately measure the effects of all influenza mutations should enhance efforts to understand and predict viral evolution.

scholarly journals Complete mapping of viral escape from neutralizing antibodies

2016 ◽  
Author(s):  
Michael B. Doud ◽  
Scott E. Hensley ◽  
Jesse D. Bloom
Keyword(s):  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Viral Evolution ◽  
The Other ◽  
Viral Escape ◽  
Amino Acid Mutation ◽  
Influenza Hemagglutinin ◽  
Complete Mapping ◽  
Protein Variants

AbstractIdentifying viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. Here we quantify how every amino-acid mutation to influenza hemagglutinin affects neutralization by monoclonal antibodies targeting several antigenic regions. Our approach involves creating all replication-competent protein variants of the virus, selecting these variants with antibody, and using deep sequencing to identify enriched mutations. These high-throughput measurements are predictive of the effects of individual mutations in traditional neutralization assays. At many residues, only some of the possible mutations escape from an antibody. For instance, at a single residue targeted by two different antibodies, we identify some mutations that escape both antibodies and other mutations that escape only one or the other. Therefore, our approach maps how viruses can escape antibodies with mutation-level sensitivity, and shows that only some mutations at antigenic residues actually alter antigenicity.

Analysis of antigenic domain of GST fused major surface protein (p30) fragments of Toxoplasma gondii

1996 ◽  
Vol 34 (2) ◽  
pp. 135 ◽  
Author(s):  
H W Nam ◽  
K S Im ◽  
E J Baek ◽  
W Y Choi ◽  
S Y Cho
Keyword(s):  
Toxoplasma Gondii ◽  
Surface Protein ◽  
Major Surface Protein ◽  
Major Surface ◽  
Antigenic Domain

scholarly journals Hide and seek: interplay between influenza viruses and B cells

2020 ◽  
Vol 32 (9) ◽  
pp. 605-611 ◽  
Author(s):  
Masayuki Kuraoka ◽  
Yu Adachi ◽  
Yoshimasa Takahashi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Surface Protein ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Native Structure ◽  
Humoral Immune ◽  
Protective Antibodies ◽  
Major Surface ◽  
And Function

Abstract Influenza virus constantly acquires genetic mutations/reassortment in the major surface protein, hemagglutinin (HA), resulting in the generation of strains with antigenic variations. There are, however, HA epitopes that are conserved across influenza viruses and are targeted by broadly protective antibodies. A goal for the next-generation influenza vaccines is to stimulate B-cell responses against such conserved epitopes in order to provide broad protection against divergent influenza viruses. Broadly protective B cells, however, are not easily activated by HA antigens with native structure, because the virus has multiple strategies to escape from the humoral immune responses directed to the conserved epitopes. One such strategy is to hide the conserved epitopes from the B-cell surveillance by steric hindrance. Technical advancement in the analysis of the human B-cell antigen receptor (BCR) repertoire has dissected the BCRs to HA epitopes that are hidden in the native structure but are targeted by broadly protective antibodies. We describe here the characterization and function of broadly protective antibodies and strategies that enable B cells to seek these hidden epitopes, with potential implications for the development of universal influenza vaccines.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

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