Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
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DOI：
10.1016/j.cell.2016.02.022
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发表时间：
2016-04-07
期刊：
影响因子：
64.5
通讯作者：
Haynes BF
中科院分区：
文献类型：
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作者：
Bonsignori M;Zhou T;Sheng Z;Chen L;Gao F;Joyce MG;Ozorowski G;Chuang GY;Schramm CA;Wiehe K;Alam SM;Bradley T;Gladden MA;Hwang KK;Iyengar S;Kumar A;Lu X;Luo K;Mangiapani MC;Parks RJ;Song H;Acharya P;Bailer RT;Cao A;Druz A;Georgiev IS;Kwon YD;Louder MK;Zhang B;Zheng A;Hill BJ;Kong R;Soto C;NISC Comparative Sequencing Program;Mullikin JC;Douek DC;Montefiori DC;Moody MA;Shaw GM;Hahn BH;Kelsoe G;Hraber PT;Korber BT;Boyd SD;Fire AZ;Kepler TB;Shapiro L;Ward AB;Mascola JR;Liao HX;Kwong PD;Haynes BF
具有来自VH 1 -2或VH 1 -46-生殖系基因的个体基因的抗体主导针对HIV-1上的CD 4结合位点（CD 4 bs）的广泛中和反应。在这里，我们定义了从感染时间的纵向采样的VH 1 -46衍生的抗体谱系的发展，成熟，中和90%的HIV-1分离株。谱系抗体CH 235（从感染时间起第41周，18%宽度）、CH 235.9（第152周，77%）和CH 235.12（第323周，90%）的结构证明成熟表位集中于CD 4 bs的构象不变部分。CH 235谱系和五个不相关的CD 4 bs谱系在表位聚焦、发展宽度的时间长度和异常水平的体细胞超突变方面的相似性表明所有CD 4 bs抗体在成熟方面的共性。幸运的是，所需的CH 235谱系超突变似乎基本上由VH 1 -46基因的内在突变性指导，该基因与VH 1 -2非常相似。我们将我们的CH 235谱系研究结果与第二种广泛中和谱系和HIV-1共同进化相结合，提出了诱导两种谱系的疫苗接种策略。
Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%) and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary levels of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.