ArticleProceedings of the National Academy of Sciences of the United States of America2017
Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
- Somatic hypermutation patterns are shaped by both motif position and sequence grammar.The EMBO journal · 2026Article
- Germline-Targeting Strategies to Induce bNAbs against HIV-1.Current HIV research · 2026Review
- Mutation-guided vaccine design: A process for developing boosting immunogens for HIV broadly neutralizing antibody induction.Cell host & microbe · 2024Article
- Breakthrough infection elicits hypermutated IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2 variants including the emerging EG.5 lineages.PLoS pathogens · 2023Article
- Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies.Nature reviews. Immunology · 2023Review
- Ancestral reconstruction reveals catalytic inactivation of activation-induced cytidine deaminase concomitant with cold water adaption in the Gadiformes bony fish.BMC biology · 2022Article
- A multi-objective based clustering for inferring BCR clonal lineages from high-throughput B cell repertoire data.PLoS computational biology · 2022Article
- Learning the statistics and landscape of somatic mutation-induced insertions and deletions in antibodies.PLoS computational biology · 2022Article
- Complementary Roles of Antibody Heavy and Light Chain Somatic Hypermutation in Conferring Breadth and Potency to the HIV-1-Specific CAP256-VRC26 bNAb Lineage.Journal of virology · 2022Article
- Contribution of rare mutational outcomes to broadly neutralizing antibodies.Acta biochimica et biophysica Sinica · 2022Review
- Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations.Cell reports · 2021Article
- In vitro evolution of antibody affinity via insertional scanning mutagenesis of an entire antibody variable region.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage.Cell host & microbe · 2020Article
- AID Overlapping and Polη Hotspots Are Key Features of Evolutionary Variation Within the Human Antibody Heavy Chain (IGHV) Genes.Frontiers in immunology · 2020Article
- Targeted selection of HIV-specific antibody mutations by engineering B cell maturation.Science (New York, N.Y.) · 2019Article
- Survival analysis of DNA mutation motifs with penalized proportional hazards.The annals of applied statistics · 2019Article
- DNA Breaks in Ig V Regions Are Predominantly Single Stranded and Are Generated by UNG and MSH6 DNA Repair Pathways.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- cAb-Rep: A Database of Curated Antibody Repertoires for Exploring Antibody Diversity and Predicting Antibody Prevalence.Frontiers in immunology · 2019Article
- Signaling control of antibody isotype switching.Advances in immunology · 2019Review
- Nomenclature of humanized mAbs: Early concepts, current challenges and future perspectives.Human antibodies · 2019Review
Corrections and comments
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Authors and funding
13 authors at 8 institutions in 1 country.
Funding
Abstract
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity. Some HIV-1-infected human subjects develop broadly neutralizing antibodies (bnAbs), such as the potent VRC01-class bnAbs, that neutralize diverse HIV-1 strains. Mature VRC01-class bnAbs, including VRC-PG04, accumulate very high SHM levels, a property that hinders development of vaccine strategies to elicit them. Because many VRC01-class bnAb SHMs are not required for broad neutralization, high overall SHM may be required to achieve certain functional SHMs. To elucidate such requirements, we used a V(D)J passenger allele system to assay, in mouse GC B cells, sequence-intrinsic SHM-targeting rates of nucleotides across substrates representing maturation stages of human VRC-PG04. We identify rate-limiting SHM positions for VRC-PG04 maturation, as well as SHM hotspots and intrinsically frequent deletions associated with SHM. We find that mature VRC-PG04 has low SHM capability due to hotspot saturation but also demonstrate that generation of new SHM hotspots and saturation of existing hotspot regions (e.g., CDR3) does not majorly influence intrinsic SHM in unmutated portions of VRC-PG04 progenitor sequences. We discuss implications of our findings for bnAb affinity maturation mechanisms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.