Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10.
Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10.
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DOI：
10.4049/jimmunol.1300770
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发表时间：
2013-08-01
期刊：
影响因子：
--
通讯作者：
Verkoczy L
中科院分区：
文献类型：
--
作者：
Chen Y;Zhang J;Hwang KK;Bouton-Verville H;Xia SM;Newman A;Ouyang YB;Haynes BF;Verkoczy L
由于免疫原无法诱导防止感染的广泛中和抗体（bnAbs），开发HIV-1疫苗一直受到阻碍。在此之前，我们用敲入蛋白（knockin， KI）小鼠表达一种典型的gp41特异性bnAb， 2F5，来证明由2F5 H链的自身反应性引发的免疫耐受，阻碍了bnAb的诱导。在这里，我们从另外两种HIV-1抗体中生成了表达H链的KI模型：4E10（另一种自我/多反应性α-gp41 bnAb）和48d (α-CD4诱导的非多反应性Ab)，并发现了类似的发育阻断，与4E10的中心b细胞缺失一致，但在48d的VH KI小鼠中没有。此外，在表达完整的2F5和4E10抗体作为BCR的KI菌株中，我们发现残余的脾脏b细胞在不同的发育阶段停滞，但表现出均匀的低表面Ig密度，升高的基础激活，对BCR连接的深刻沉默反应，并且当作为杂交瘤单克隆细胞系捕获时，保持其双重（gp41/脂质）亲和力和中和HIV-1的能力，建立了能量在抑制残余的2F5或4E10表达b细胞中的关键作用。重要的是，naïve 2F5和4E10 KI菌株的血清igg分别选择性地消除gp41和脂质结合，这表明表达2F5或4E10作为BCR的b细胞对不同的宿主抗原谱表现出特异性，包括2F5 BCR+ b细胞（即，而不是4E10 BCR+ b细胞）与自身抗原中模仿gp41中和表位的残基的选择性相互作用。
Developing an HIV-1 vaccine has been hampered by the inability of immunogens to induce broadly neutralizing antibodies (bnAbs) that protect against infection. Previously, we used knockin (KI) mice expressing a prototypical gp41-specific bnAb, 2F5, to demonstrate that immunological tolerance triggered by self-reactivity of the 2F5 H chain, impedes bnAb induction. Here, we generate KI models expressing H chains from two other HIV-1 Abs: 4E10 (another self-/polyreactive, α-gp41 bnAb) and 48d (an α-CD4 inducible, non-polyreactive Ab), and find a similar developmental blockade consistent with central B-cell deletion in 4E10, but not in 48d VH KI mice. Furthermore, in KI strains expressing the complete 2F5 and 4E10 Abs as BCRs, we find that residual splenic B-cells arrest at distinct developmental stages, yet exhibit uniformly low surface Ig densities, elevated basal activation, profoundly muted responses to BCR ligation, and when captured as hybridoma mAb lines, maintain their dual (gp41/lipid) affinities and capacities to neutralize HIV-1, establishing a key role for anergy in suppressing residual 2F5 or 4E10-expressing B-cells. Importantly, serum IgGs from naïve 2F5 and 4E10 KI strains selectively eliminate gp41 and lipid binding, respectively, suggesting B-cells expressing 2F5 or 4E10 as BCRs exhibit specificity for a distinct spectrum of host antigens, including selective interactions by 2F5 BCR+ B-cells (i.e., and not 4E10 BCR+ B-cells) with residues in self-antigen(s) that mimic its gp41 neutralization epitope.
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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
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56.9
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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