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However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a V\n                    <jats:sub>H<\/jats:sub>\n                    1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration\u2009=\u20090.059\u2009\u00b5g\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    , breadth\u2009=\u200998.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration\u2009=\u20090.082\u2009\u00b5g\u2009ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    , breadth\u2009=\u200998.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of &gt;93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.\n                  <\/jats:p>","DOI":"10.1038\/s41590-025-02286-5","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T09:03:53Z","timestamp":1759741433000},"page":"2016-2029","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy"],"prefix":"10.1038","volume":"26","author":[{"given":"Lutz","family":"Gieselmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-3449","authenticated-orcid":false,"given":"Andrew 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