{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:55:45Z","timestamp":1791204945838,"version":"4.1.0"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01AI138212"],"award-info":[{"award-number":["P01AI138212"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["UM1AI144462"],"award-info":[{"award-number":["UM1AI144462"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that bind relatively conserved regions of the otherwise highly variable envelope glycoprotein. Among these, VRC01-class bNAbs are a reproducible antibody class that bind the CD4-binding site through genetic features encoded by the VH1-2 heavy chain and a light chain containing a rare five-amino-acid-long complementarity-determining region 3 (CDRL3). We previously developed a germline-targeting immunogen, iv4\/iv9, derived from anti-idiotypic monoclonal antibodies (ai-mAbs) that target these genetic signatures of VRC01-class bNAbs. Here, we applied structure-guided modification of iv4\/iv9 that improved selective binding to VRC01 precursors\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and carried out immunizations in ATX-GK mice. These mice are transgenic for human antibody genes, producing a diverse, genetically human antibody repertoire. We found that ATX-GK mice harbor VRC01 precursors at frequencies lower than those found in humans. Class-switched VRC01 precursors were detected in a minority of mice immunized with a modified iv4\/iv9 immunogen. Collectively, these results indicate that the ATX-GK mice have utility to evaluate VRC01-class germline-targeting immunogens but are a stringent model due to a low frequency of VRC01-class B cells. They further suggest that the ai-mAb immunogens evaluated herein will require further optimization to reproducibly prime VRC01-class B cells in ATX-GK mice.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that bind relatively conserved regions of the otherwise highly variable envelope glycoprotein. Among these, VRC01-class bNAbs are a reproducible antibody class that bind the CD4-binding site through genetic features encoded by the VH1-2 heavy chain and a light chain containing a rare five-amino-acid-long complementarity-determining region 3 (CDRL3). We previously developed a germline-targeting immunogen, iv4\/iv9, derived from anti-idiotypic monoclonal antibodies that target these genetic signatures of VRC01-class bNAbs. Here, we evaluate the B-cell response to immunization with iv4\/iv9 and with a structure-guided modified iv4\/iv9 in ATX-GK mice. These modifications are intended to improve the selectivity of VRC01 precursors in a diverse polyclonal B cell repertoire. These mice are transgenic for human antibody genes, producing a diverse, genetically human antibody repertoire. We found that ATX-GK mice harbor VRC01 precursors at frequencies lower than those found in humans. Class-switched VRC01 precursors were detected in a minority of animals immunized with the modified iv4\/iv9. Collectively, these results indicate that although the iv4\/iv9 immunogen did not reproducibly elicit VRC01-class B cells, ATX-GK mice have utility to evaluate VRC01-class germline-targeting immunogens but are a stringent model due to a low frequency of VRC01-class B cells.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00317-26","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:01:21Z","timestamp":1788267681000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating an anti-idiotype derived germline-targeting immunogen designed to elicit VRC01-class precursors in human antibody transgenic mice"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1394-783X","authenticated-orcid":false,"given":"Crystal B.","family":"Chhan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]},{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Global Health, University of Washington","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsin","family":"Wan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wilcox-King","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Homad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas T.","family":"Aldridge","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Iureniev","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1106-7097","authenticated-orcid":true,"given":"Leonidas","family":"Stamatatos","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-6859","authenticated-orcid":true,"given":"Andrew T.","family":"McGuire","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/007ps6h72","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center","place":["Seattle, USA"]},{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Global Health, University of Washington","place":["Seattle, USA"]},{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine and Pathology, University of Washington","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"World Health Organization. 2025. HIV and AIDS 2025 [updated July 15 2025; cited 2025 October 11]. Available from: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hiv-aids"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12075"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055515"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12509"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1187659"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207532"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07930"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207227"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.004"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.027"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.061"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192819"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1208984109"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00754-11"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/72309"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.17.8340-8347.2001"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10660"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3471"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00210-15"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2031738"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18929"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303682110"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.012"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.007"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13783"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003106"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1234150"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122824"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101003"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.08.016"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161160"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.005"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.071"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109084"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.11.023"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-025-01235-5"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac5894"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat0381"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2026.102618"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525510113"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05371-z"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.03.026"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1259206"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.17.9781"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf1152"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190446"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2007.09.017"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.166.3.637"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.152.7.3467"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2217883120"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.3.951"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni788"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah3945"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adn0223"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.add6502"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-021-00376-7"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13036-022-00315-7"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3027"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1087267"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae412"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2025.04.013"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.06.004"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.09.007"},{"key":"e_1_3_5_65_2","unstructured":"Alloy Therapeutics Inc. 2025. Alloy therapeutics 2025 [June 26 2025]. Available from: https:\/\/alloytx.com"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn316"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37688"}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00317-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00317-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:37:40Z","timestamp":1791203860000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msphere.00317-26"}},"subtitle":[],"editor":[{"given":"Hao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":66,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,29]]}},"alternative-id":["10.1128\/msphere.00317-26"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00317-26","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00317-26"}}