Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies.
Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies.
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DOI：
10.1016/j.cell.2016.08.005
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发表时间：
2016-09-08
期刊：
影响因子：
64.5
通讯作者：
Schief, William R.
中科院分区：
文献类型：
--
作者：
Briney, Bryan;Sok, Devin;Jardine, Joseph G.;Kulp, Daniel W.;Skog, Patrick;Menis, Sergey;Jacak, Ronald;Kalyuzhniy, Oleksandr;de Val, Natalia;Sesterhenn, Fabian;Le, Khoa M.;Ramos, Alejandra;Jones, Meaghan;Saye-Francisco, Karen L.;Blane, Tanya R.;Spencer, Skye;Georgeson, Erik;Hu, Xiaozhen;Ozorowski, Gabriel;Adachi, Yumiko;Kubitz, Michael;Sarkar, Anita;Wilson, Ian A.;Ward, Andrew B.;Nemazee, David;Burton, Dennis R.;Schief, William R.
广泛中和抗体（bnAb）的诱导是HIV疫苗开发的主要目标。VRC 01类bnAb是重要的疫苗先导物，因为其被工程化引发免疫原靶向的前体B细胞在人类中相对常见。这种引发免疫原已经在动物模型中证明了启动bnAb应答的能力，但尚未显示出对bnAb发育的回忆和成熟。在这里，我们报告了增强免疫原的发展，旨在指导先前引发的VRC 01类前体的遗传和功能成熟。加强表达生殖系VRC 01重链的转基因小鼠模型产生了近天然分离株（N276 A）的广泛中和和完全天然HIV的弱中和。功能和遗传特征表明，加强的mAb与部分成熟的VRC 01类抗体一致，并将它们置于导致成熟VRC 01类bnAb的成熟轨迹上。结果显示了简化顺序免疫如何引导HIV bnAb应答的成熟。设计加强免疫原以遵循VRC 01类种系靶向初免加强抗体选择性掺入VRC 01类体细胞突变连续加强引发VRC 01类mAb，广泛中和N276 A病毒疫苗引发的VRC 01类mAb中和一种完全天然的HIV分离株开发加强HIV包膜免疫原，旨在引导VRC 01的遗传和功能成熟-bnAb类为设计有效的HIV疫苗提供了路线图。
Induction of broadly neutralizing antibodies (bnAbs) is a primary goal of HIV vaccine development. VRC01-class bnAbs are important vaccine leads because their precursor B cells targeted by an engineered priming immunogen are relatively common among humans. This priming immunogen has demonstrated the ability to initiate a bnAb response in animal models, but recall and maturation toward bnAb development has not been shown. Here, we report the development of boosting immunogens designed to guide the genetic and functional maturation of previously primed VRC01-class precursors. Boosting a transgenic mouse model expressing germline VRC01 heavy chains produced broad neutralization of near-native isolates (N276A) and weak neutralization of fully native HIV. Functional and genetic characteristics indicate that the boosted mAbs are consistent with partially mature VRC01-class antibodies and place them on a maturation trajectory that leads toward mature VRC01-class bnAbs. The results show how reductionist sequential immunization can guide maturation of HIV bnAb responses. Designed boosting immunogens to follow a VRC01-class germline-targeting prime Boosted Abs selectively incorporate VRC01-class somatic mutations Sequential boosts elicit VRC01-class mAbs with broad neutralization of N276A viruses Vaccine-elicited VRC01-class mAbs neutralize one fully native HIV isolate Development of boosting HIV envelope immunogens designed to guide the genetic and functional maturation of VRC01-class bnAbs provides a roadmap for the design of an effective HIV vaccine.
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影响因子：
32.4
作者：
Falkowska, Emilia;Le, Khoa M.;Ramos, Alejandra;Doores, Katie J.;Lee, Jeong Hyun;Blattner, Claudia;Ramirez, Alejandro;Derking, Ronald;van Gils, Marit J.;Liang, Chi-Hui;Mcbride, Ryan;von Bredow, Benjamin;Shivatare, Sachin S.;Wu, Chung-Yi;Chan-Hui, Po-Ying;Liu, Yan;Feizi, Ten;Zwick, Michael B.;Koff, Wayne C.;Seaman, Michael S.;Swiderek, Kristine;Moore, John P.;Evans, David;Paulson, James C.;Wong, Chi-Huey;Ward, Andrew B.;Wilson, Ian A.;Sanders, Rogier W.;Poignard, Pascal;Burton, Dennis R.
通讯作者：
Burton, Dennis R.
影响因子：
46.9
作者：
通讯作者：
--
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
影响因子：
64.8
作者：
Caskey M;Klein F;Lorenzi JC;Seaman MS;West AP Jr;Buckley N;Kremer G;Nogueira L;Braunschweig M;Scheid JF;Horwitz JA;Shimeliovich I;Ben-Avraham S;Witmer-Pack M;Platten M;Lehmann C;Burke LA;Hawthorne T;Gorelick RJ;Walker BD;Keler T;Gulick RM;Fätkenheuer G;Schlesinger SJ;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
5.4
作者：
Hraber, Peter;Korber, Bette T.;Montefiori, David C.
通讯作者：
Montefiori, David C.