![]() This provides strong rationale for developing immunogens that favor bnAb lineages bearing “neutralization-only” mutations into current HIV-1 vaccine designs. Our results demonstrate that broad neutralization activity and autoreactivity in the CH103-106 bnAb lineage can be governed by a few, distinct mutations during maturation. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. 6Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, Guangdongg, China.5Institute of Molecular and Medical Virology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.4Applied Biomedical Science Institute, San Diego, CA, United States. ![]() 3School of Life Sciences, Fudan University, Shanghai, China.2Department of Immunology, Duke University Medical Center, Durham, NC, United States.1Department of Medicine, Duke University Medical Center, Durham, NC, United States.Xiaojun Li 1 Dongmei Liao 2 Zhengyang Li 3 Jixi Li 3 Marilyn Diaz 4 Laurent Verkoczy 4* Feng Gao 1,5,6*
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