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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:p>\n                    Antibody heavy chain (HC) and light chain (LC) variable region exons are assembled by V(D)J recombination. V(D)J junctional regions encode complementarity-determining-region 3 (CDR3), an antigen-contact region immensely diversified through nontemplated nucleotide additions (\u201cN-regions\u201d) by terminal deoxynucleotidyl transferase (TdT). HIV-1 vaccine strategies seek to elicit human HIV-1 broadly neutralizing antibodies (bnAbs), such as the potent CD4-binding site VRC01-class bnAbs. Mice with primary B cells that express receptors (BCRs) representing bnAb precursors are used as vaccination models. VRC01-class bnAbs uniformly use human HC V\n                    <jats:sub>H<\/jats:sub>\n                    1-2 and commonly use human LCs V\u03ba3-20 or V\u03ba1-33 associated with an exceptionally short 5-amino-acid (5-aa) CDR3. Prior VRC01-class models had nonphysiological precursor levels and\/or limited precursor diversity. Here, we describe VRC01-class rearranging mice that generate more physiological primary VRC01-class BCR repertoires via rearrangement of V\n                    <jats:sub>H<\/jats:sub>\n                    1-2, as well as V\u03ba1-33 and\/or V\u03ba3-20 in association with diverse CDR3s. Human-like TdT expression in mouse precursor B cells increased LC CDR3 length and diversity and also promoted the generation of shorter LC CDR3s via N-region suppression of dominant microhomology-mediated V\u03ba-to-J\u03ba joins. Priming immunization with eOD-GT8 60mer, which strongly engages VRC01 precursors, induced robust VRC01-class germinal center B cell responses. V\u03ba3-20-based responses were enhanced by N-region addition, which generates V\u03ba3-20-to-J\u03ba junctional sequence combinations that encode VRC01-class 5-aa CDR3s with a critical E residue. VRC01-class-rearranging models should facilitate further evaluation of VRC01-class prime and boost immunogens. These new VRC01-class mouse models establish a prototype for the generation of vaccine-testing mouse models for other HIV-1 bnAb lineages that employ different HC or LC Vs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2217883120","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T16:25:01Z","timestamp":1672158301000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":34,"title":["Humanized V(D)J-rearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7362-5445","authenticated-orcid":false,"given":"Sai","family":"Luo","sequence":"first","affiliation":[{"name":"HHMI, Boston Children's Hospital, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Department of 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