Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer.
Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer.
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DOI：
10.1371/journal.ppat.1004767
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Sanders RW
中科院分区：
文献类型：
--
作者：
Derking R;Ozorowski G;Sliepen K;Yasmeen A;Cupo A;Torres JL;Julien JP;Lee JH;van Montfort T;de Taeye SW;Connors M;Burton DR;Wilson IA;Klasse PJ;Ward AB;Moore JP;Sanders RW
三聚体包膜（Env）刺突是疫苗设计工作的重点，旨在产生广泛中和抗体（bNAb），以防止HIV-1感染。三个最近的发展促进了Env三聚体的抗原结构的彻底研究：1）针对多个不同表位的许多bNAb的分离; 2）表达大多数bNAb表位的可溶性三聚体模拟物BG 505 SOSIP.664 gp 140的产生; 3）涉及标记的三聚体的定向固定的简易结合测定。使用这些工具，我们通过抗体交叉竞争生成了三聚体的抗原图。我们的分析描绘了三个明确定义的表位簇（CD 4结合位点，四级V1 V2和Asn 332为中心的寡聚甘露糖补丁）和新的表位在gp 120-gp 41接口。它还确定了这些集群之间的关系。除了表位重叠之外，我们还定义了抗体可以交叉竞争的三种方式：来自与邻近但不重叠的表位结合的空间竞争（例如，PGT 151抑制8ANC 195结合）;变构抑制（例如，PGT 145对1 NC 9、8ANC 195、PGT 151和CD 4结合的抑制）;以及通过聚糖的重定向的竞争（例如，PGT 135对CD 4 bs bNAb的抑制，以及CD 4 bs bNAb对8ANC 195的抑制）。我们进一步证明，bNAb的结合可以是复杂的，往往影响其他几个领域的三聚体表面以外的表位。Env三聚体的抗原结构和表位相互关系的这种广泛分析应有助于设计基于bNAb的疗法和旨在诱导bNAb的疫苗。针对HIV-1包膜糖蛋白三聚体上各种表位的新的广泛中和抗体的发现及其结构知识的增加正在指导疫苗设计。为了增加我们对不同表位之间相互关系的理解，我们使用各种技术生成了三聚体的详细抗原图。我们已经发现了抗体可以影响彼此结合的各种机制。由此产生的抗原图谱应进一步有助于设计HIV-1疫苗，以诱导广泛中和抗体，并设计用于治疗用途的这种抗体的鸡尾酒。
The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs. The discovery of new broadly neutralizing antibodies against various epitopes on the HIV-1 envelope glycoprotein trimer and increased knowledge of its structure are guiding vaccine design. To increase our understanding of the interrelationships among the different epitopes, we generated a detailed antigenic map of the trimer using a variety of techniques. We have uncovered various mechanisms whereby antibodies can influence each other’s binding. The resulting antigenic map should further aid in design of HIV-1 vaccines to induce broadly neutralizing antibodies and in devising cocktails of such antibodies for therapeutic use.
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影响因子：
16.8
作者：
Kong, Leopold;Lee, Jeong Hyun;Doores, Katie J.;Murin, Charles D.;Julien, Jean-Philippe;McBride, Ryan;Liu, Yan;Marozsan, Andre;Cupo, Albert;Klasse, Per-Johan;Hoffenberg, Simon;Caulfield, Michael;King, C. Richter;Hua, Yuanzi;Le, Khoa M.;Khayat, Reza;Deller, Marc C.;Clayton, Thomas;Tien, Henry;Feizi, Ten;Sanders, Rogier W.;Paulson, James C.;Moore, John P.;Stanfield, Robyn L.;Burton, Dennis R.;Ward, Andrew B.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
DOI：
10.1084/jem.20120423
发表时间：
2012-07-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Klein F;Gaebler C;Mouquet H;Sather DN;Lehmann C;Scheid JF;Kraft Z;Liu Y;Pietzsch J;Hurley A;Poignard P;Feizi T;Morris L;Walker BD;Fätkenheuer G;Seaman MS;Stamatatos L;Nussenzweig MC
通讯作者：
Nussenzweig MC
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：
3
作者：
Ogura, T;Iwasaki, K;Sato, C
通讯作者：
Sato, C
影响因子：
56.9
作者：
BURTON, DR;PYATI, J;BARBAS, CF
通讯作者：
BARBAS, CF