Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows.
Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows.
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DOI：
10.1038/nature23301
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发表时间：
2017-08-03
期刊：
影响因子：
64.8
通讯作者：
Burton DR
中科院分区：
文献类型：
--
作者：
Sok D;Le KM;Vadnais M;Saye-Francisco KL;Jardine JG;Torres JL;Berndsen ZT;Kong L;Stanfield R;Ruiz J;Ramos A;Liang CH;Chen PL;Criscitiello MF;Mwangi W;Wilson IA;Ward AB;Smider VV;Burton DR
迄今为止，还没有任何免疫原能够在人类或动物模型中可靠地引发针对 HIV 的广泛中和抗体 (bnAb)。抗原模拟 HIV 包膜糖蛋白 (Env) 的免疫原 (BG505 SOSIP) 设计的进展改善了兔子和猕猴中强效分离特异性抗体反应的引发，但迄今为止未能诱导 bnAb。造成这种失败的一个可能原因是，相对于暴露的可变表位，相关抗体库不太适合靶向 Env 上有些封闭的保守表位区域。为了检验这一假设，我们用 BG505 SOSIP 对四头奶牛进行了免疫。牛的抗体库包含长的第三重链互补决定区 (HCDR3)，其超长子集的长度可达 70 多个氨基酸。值得注意的是，BG505 SOSIP 免疫导致所有四头牛快速引发广泛且有效的血清抗体反应。对一头牛的纵向血清分析显示，中和宽度（20%，n = 117 个跨进化枝分离株）在 42 天内发展，并在 381 天发展到 96% 宽度（n = 117）。从这头牛中分离出的单克隆抗体 (mAb) 含有 60 个氨基酸的超长 HCDR3，可中和 72% 的跨进化枝分离株 (n = 117)，有效中值 IC50 为 0.028 μg/ml。我们注意到，广度是用单一三聚体免疫原引发的，不需要额外的包膜多样性。奶牛的免疫可能提供一种快速产生抗体预防剂和治疗剂的途径，以应对已经进化出避免人类抗体反应的疾病病原体。
No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env) have improved the elicitation of potent isolate-specific Ab responses in rabbits and macaques, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody (mAb) isolated from this cow harbored an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg/ml. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.
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影响因子：
6.7
作者：
Sanders RW;Derking R;Cupo A;Julien JP;Yasmeen A;de Val N;Kim HJ;Blattner C;de la Peña AT;Korzun J;Golabek M;de Los Reyes K;Ketas TJ;van Gils MJ;King CR;Wilson IA;Ward AB;Klasse PJ;Moore JP
通讯作者：
Moore JP
影响因子：
6.7
作者：
Jardine JG;Sok D;Julien JP;Briney B;Sarkar A;Liang CH;Scherer EA;Henry Dunand CJ;Adachi Y;Diwanji D;Hsueh J;Jones M;Kalyuzhniy O;Kubitz M;Spencer S;Pauthner M;Saye-Francisco KL;Sesterhenn F;Wilson PC;Galloway DM;Stanfield RL;Wilson IA;Burton DR;Schief WR
通讯作者：
Schief WR
DOI：
10.1073/pnas.1415789111
发表时间：
2014-12-09
影响因子：
11.1
作者：
Sok, Devin;van Gils, Marit J.;Burton, Dennis R.
通讯作者：
Burton, Dennis R.
影响因子：
3
作者：
Ogura, T;Iwasaki, K;Sato, C
通讯作者：
Sato, C
影响因子：
4.4
作者：
Saini, SS;Farrugia, W;Kaushik, AK
通讯作者：
Kaushik, AK