Dataset Information

Convergent Evolution in Breadth of Two V_H6-1-Encoded Influenza Antibody Clonotypes from a Single Donor.

ABSTRACT: Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain V_H6-1. We describe two genetically similar V_H6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutralization activity. One clonotype evolved from a germline precursor recognizing influenza group 1 subtypes to gain breadth to group 2 subtypes. The other clonotype recognized group 2 subtypes and developed binding to group 1 subtypes through somatic hypermutation. Crystal structures reveal that the specificity differences are primarily mediated by complementarity-determining region H3 (CDR H3). Thus, while V_H6-1 provides a framework for development of HA stem-directed bnAbs, sequence differences in CDR H3 junctional regions during VDJ recombination can alter reactivity and evolutionary pathways toward increased breadth.

SUBMITTER: Wu NC

PROVIDER: S-EPMC7486241 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Convergent Evolution in Breadth of Two VH6-1-Encoded Influenza Antibody Clonotypes from a Single Donor.

Wu Nicholas C NC Andrews Sarah F SF Raab Julie E JE O'Connell Sarah S Schramm Chaim A CA Ding Xintao X Chambers Michael J MJ Leung Kwanyee K Wang Lingshu L Zhang Yi Y Mascola John R JR Douek Daniel C DC Ledgerwood Julie E JE McDermott Adrian B AB Wilson Ian A IA

Cell host & microbe 20200702 3

Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain VH6-1. We describe two genetically similar VH6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutral ...[more]

PMID: 32619441

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Project description:BackgroundVaccines dramatically affect an individual's adaptive immune system and thus provide an excellent means to study human immunity. Upon vaccination, the B cells that express antibodies (Abs) that happen to bind the vaccine are stimulated to proliferate and undergo mutagenesis at their Ab locus. This process may alter the composition of B cell lineages within an individual, which are known collectively as the antibody repertoire (AbR). Antibodies are also highly expressed in whole blood, potentially enabling RNA sequencing (RNA-seq) technologies to query this diversity. Less is known about the diversity of AbR responses across individuals to a given vaccine and if individuals tend to yield a similar response to the same antigenic stimulus.MethodsHere we implement a bioinformatic pipeline that extracts the AbR information from a time-series RNA-seq dataset of five patients who were administered a seasonal trivalent influenza vaccine (TIV). We harness the detailed time-series nature of this dataset and use methods based in functional data analysis (FDA) to identify the Abs that respond to the vaccine. We then design and implement rigorous statistical tests in order to ask whether or not these patients exhibit a convergent AbR response to the same TIV.ResultsWe find that high-resolution time-series data can be used to help identify the Abs that respond to an antigenic stimulus and that this response can exhibit a convergent nature across patients inoculated with the same vaccine. However, correlations in AbR diversity among individuals prior to inoculation can confound inference of a convergent signal unless it is taken into account.ConclusionsWe developed a framework to identify the elements of an AbR that respond to an antigen. This information could be used to understand the diversity of different immune responses in different individuals, as well as to gauge the effectiveness of the immune response to a given stimulus within an individual. We also present a framework for testing a convergent hypothesis between AbRs; a hypothesis that is more difficult to test than previously appreciated. Our discovery of a convergent signal suggests that similar epitopes do select for antibodies with similar sequence characteristics.

Dataset Information

Convergent Evolution in Breadth of Two V_H6-1-Encoded Influenza Antibody Clonotypes from a Single Donor.

Publications

Convergent Evolution in Breadth of Two V<sub>H</sub>6-1-Encoded Influenza Antibody Clonotypes from a Single Donor.

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