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.

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 Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Science ◽  
2021 ◽  
Vol 371 (6531) ◽  
pp. 850-854 ◽  
Author(s):  
Tyler N. Starr ◽  
Allison J. Greaney ◽  
Amin Addetia ◽  
William W. Hannon ◽  
Manish C. Choudhary ◽  
...  
Keyword(s):  
Amino Acid ◽  
Infected Patient ◽  
Viral Escape ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Amino Acid Mutation ◽  
The Individual ◽  
Viral Surveillance ◽  
Single Amino Acid Mutation

Antibodies are a potential therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the risk of the virus evolving to escape them remains unclear. Here we map how all mutations to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. These complete maps uncover a single amino acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies, REGN10933 and REGN10987, targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2 and during in vitro viral escape selections. Finally, the maps reveal that mutations escaping the individual antibodies are already present in circulating SARS-CoV-2 strains. These complete escape maps enable interpretation of the consequences of mutations observed during viral surveillance.

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 Possible Future Monoclonal Antibody (mAb)-Based Therapy against Arbovirus Infections

2013 ◽  
Vol 2013 ◽  
pp. 1-21 ◽  
Author(s):  
Giuseppe Sautto ◽  
Nicasio Mancini ◽  
Giacomo Gorini ◽  
Massimo Clementi ◽  
Roberto Burioni
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Side Effects ◽  
Antiviral Activity ◽  
The Other ◽  
Viral Escape ◽  
Passive Immunotherapy ◽  
Medical Need

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminaryin vitroandin vivomodels of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.

scholarly journals In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2–Spike RBD Interface

2021 ◽  
Vol 22 (4) ◽  
pp. 1695
Author(s):  
Bruno O. Villoutreix ◽  
Vincent Calvez ◽  
Anne-Geneviève Marcelin ◽  
Abdel-Majid Khatib
Keyword(s):  
Amino Acid ◽  
South African ◽  
In Silico ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Spike Protein ◽  
Amino Acid Substitutions ◽  
The South ◽  
African Strain ◽  
The Uk

SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike–ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure–function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.

scholarly journals Selective Cytotoxicity of Carboxypeptidase-activated Methotrexate ex-Peptides

Pteridines ◽  
1989 ◽  
Vol 1 (1) ◽  
pp. 65-69 ◽  
Author(s):  
Karin S. Vitols ◽  
Yolanda D. Montejano ◽  
Ulrike Kuefner ◽  
F. M. Huennekens
Keyword(s):  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Suspension Culture ◽  
Parent Drug ◽  
Model System ◽  
The Other ◽  
Carboxypeptidase A ◽  
Selective Cytotoxicity ◽  
Cell Kill ◽  
Semi Solid

Summary Methotrexate ex-pep tides (derivatives in which an amino acid is linked covalently to the ex-carboxyl of the glutamate residue on the parent drug) can be hydrolyzed by specific carboxypeptidases to yield free Methotrexate (MTX) and the corresponding amino acid. Studies with L12l0 cells in suspension culture have shown that the MTX pep tides can serve as "pro-drugs": Because of their inability to be taken up by cells, they are relatively non-toxic. When co-administered with appropriate carboxypeptidases, however, they become equitoxic with MTX. In the present investigation, the potential of the MTX-ala/carboxypeptidase A combination for providing regional cytotoxicity was demonstrated in a model system involving L12l0 cells propagated in semi-solid agarose. When cells and one of the components (MTX peptide or carboxypeptidase) were distributed uniformly throughout the agarose, and the other component was immobilized at the center, a discrete zone of cell kill radiated from the fixed component. These results suggest the possibility of developing a new mode of cancer chemotherapy involving circulating MTX peptides in conjunction with carboxypeptidases linked covalently to tumor-targeted monoclonal antibodies.

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 Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

2018 ◽  
Vol 115 (29) ◽  
pp. 7569-7574 ◽  
Author(s):  
Fernando Aleman ◽  
Netanel Tzarum ◽  
Leopold Kong ◽  
Kenna Nagy ◽  
Jiang Zhu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Structural Analysis ◽  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
The Other ◽  
Maturation Process ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Candidates ◽  
Rational Vaccine Design ◽  
Hairpin Conformation

Elicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. Six of the mAbs recognize the conserved E2 antigenic site 412–423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates.

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 Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

2020 ◽  
Author(s):  
Tyler N. Starr ◽  
Allison J. Greaney ◽  
Amin Addetia ◽  
William W. Hannon ◽  
Manish C. Choudhary ◽  
...  
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Infected Patient ◽  
Viral Escape ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Amino Acid Mutation ◽  
Frontline Therapy ◽  
Viral Surveillance ◽  
Single Amino Acid Mutation

Antibodies are becoming a frontline therapy for SARS-CoV-2, but the risk of viral evolutionary escape remains unclear. Here we map how all mutations to SARS-CoV-2’s receptor-binding domain (RBD) affect binding by the antibodies in Regeneron’s REGN-COV2 cocktail and Eli Lilly’s LY-CoV016. These complete maps uncover a single amino-acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2, as well as in lab viral escape selections. Finally, the maps reveal that mutations escaping each individual antibody are already present in circulating SARS-CoV-2 strains. Overall, these complete escape maps enable immediate interpretation of the consequences of mutations observed during viral surveillance.

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