Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies.
Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies.
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DOI：
10.3389/fimmu.2022.977630
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发表时间：
2022
影响因子：
7.3
通讯作者：
Gao, Feng
中科院分区：
文献类型：
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作者：
Li, Xiaojun;Liao, Dongmei;Li, Zhengyang;Li, Jixi;Diaz, Marilyn;Verkoczy, Laurent;Gao, Feng
许多已知的最好的HIV-1广泛中和抗体（bnAb）具有多聚/自身反应性特征，其不利于正常B细胞发育和成熟，这在开发有效的HIV-1疫苗中构成了主要障碍。解决这个问题的关键是了解bnAb获得的中和宽度赋予突变是否以及在多大程度上有助于其自身反应性。在这里，我们回复突变了由原型CD 4结合位点定向的bnAb谱系CH 103 -106在其后期成熟步骤期间产生的所有已知变化。引人注目的是，在检测的29种突变中，只有4种对增加自身反应性至关重要，对中和作用影响极小或没有影响。此外，这些残基中的三个聚集在重链互补决定区2（HCDR 2）中。我们的结果表明，广泛的中和活性和自身反应性在CH 103 -106 bnAb谱系可以由几个不同的突变在成熟过程中。这为开发有利于携带“仅中和”突变的bnAb谱系进入当前HIV-1疫苗设计的免疫原提供了强有力的理论基础。
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. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). 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. This provides strong rationale for developing immunogens that favor bnAb lineages bearing “neutralization-only” mutations into current HIV-1 vaccine designs.
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影响因子：
64.8
作者：
Huang J;Ofek G;Laub L;Louder MK;Doria-Rose NA;Longo NS;Imamichi H;Bailer RT;Chakrabarti B;Sharma SK;Alam SM;Wang T;Yang Y;Zhang B;Migueles SA;Wyatt R;Haynes BF;Kwong PD;Mascola JR;Connors M
通讯作者：
Connors M
DOI：
10.1126/science.aao3859
发表时间：
2018-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burnett DL;Langley DB;Schofield P;Hermes JR;Chan TD;Jackson J;Bourne K;Reed JH;Patterson K;Porebski BT;Brink R;Christ D;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
17.1
作者：
Andrews SF;Huang Y;Kaur K;Popova LI;Ho IY;Pauli NT;Henry Dunand CJ;Taylor WM;Lim S;Huang M;Qu X;Lee JH;Salgado-Ferrer M;Krammer F;Palese P;Wrammert J;Ahmed R;Wilson PC
通讯作者：
Wilson PC
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
影响因子：
46.9
作者：
通讯作者：
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