{"doi":"10.17615/95wd-ch11","title":"Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies","abstract":"Induction of HIV-1 broad neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development but has remained challenging partially due to unusual traits of bnAbs, including high somatic hypermutation (SHM) frequencies and in-frame insertions and deletions (indels). Here we examined the propensity and functional requirement for indels within HIV-1 bnAbs. High-throughput sequencing of the immunoglobulin (Ig) VHDJH genes in HIV-1 infected and uninfected individuals revealed that the indel frequency was elevated among HIV-1-infected subjects, with no unique properties attributable to bnAb-producing individuals. This increased indel occurrence depended only on the frequency of SHM point-mutations. Indel-encoded regions were generally proximal to antigen binding sites. Additionally, reconstruction of a HIV-1 CD4-binding site bnAb clonal lineage revealed that a large compound VHDJH indel was required for bnAb activity. Thus, vaccine development should focus on designing regimens targeted at sustained activation of bnAb lineages to achieve the required SHM and indel events.","journal":"UNC Libraries","year":2020,"id":139595,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":258350,"name":"S. Munir Alam","orcid":"0000-0003-0941-0703","position":1,"is_corresponding":false},{"id":280565,"name":"Thomas B. Kepler","orcid":"0000-0002-1383-6865","position":2,"is_corresponding":false},{"id":36867,"name":"Lynn Morris","orcid":"0000-0003-3961-7828","position":3,"is_corresponding":false},{"id":603131,"name":"Krissey E. Lloyd","orcid":null,"position":4,"is_corresponding":false},{"id":603132,"name":"Rekha Bhaskarabhatla","orcid":null,"position":5,"is_corresponding":false},{"id":55768,"name":"Andrew Fire","orcid":"0000-0001-6217-8312","position":6,"is_corresponding":false},{"id":592365,"name":"Ruijun Zhang","orcid":"0000-0002-2342-8232","position":7,"is_corresponding":false},{"id":490874,"name":"Xueling Wu","orcid":"0000-0002-9752-3734","position":8,"is_corresponding":false},{"id":598466,"name":"Robert E. Parks","orcid":"0000-0002-2254-2332","position":9,"is_corresponding":false},{"id":325734,"name":"Emmanuel B. Walter","orcid":"0000-0001-6502-6736","position":10,"is_corresponding":false},{"id":249712,"name":"Myron S. Cohen","orcid":"0000-0001-5917-9664","position":11,"is_corresponding":false},{"id":280566,"name":"Garnett Kelsoe","orcid":"0000-0002-8770-040X","position":12,"is_corresponding":false},{"id":603133,"name":"Jamie Pritchett","orcid":null,"position":13,"is_corresponding":false},{"id":601089,"name":"Kara Anasti","orcid":"0000-0002-1854-743X","position":14,"is_corresponding":false},{"id":603134,"name":"Shelley Stewart","orcid":null,"position":15,"is_corresponding":false},{"id":592757,"name":"Salim S.Abdool Karim","orcid":null,"position":16,"is_corresponding":false},{"id":603135,"name":"Erika Solomon","orcid":null,"position":17,"is_corresponding":false},{"id":475545,"name":"Christina Stolarchuk","orcid":"0000-0002-1429-5212","position":18,"is_corresponding":false},{"id":596134,"name":"Hua Liao","orcid":"0000-0002-1202-5577","position":19,"is_corresponding":false},{"id":603136,"name":"Emma Friberg","orcid":null,"position":20,"is_corresponding":false},{"id":96347,"name":"Barton F. 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