Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.
Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.
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DOI：
10.1016/j.xcrm.2023.101003
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发表时间：
2023-04-18
影响因子：
14.3
通讯作者：
Sanders, Rogier W.
中科院分区：
文献类型：
--
作者：
Caniels, Tom G.;Medina-Ramirez, Max;Zhang, Jinsong;Sarkar, Anita;Kumar, Sonu;LaBranche, Alex;Derking, Ronald;Allen, Joel D.;Snitselaar, Jonne L.;Capella-Pujol, Joan;Sanchez, Ivan del Moral;Yasmeen, Anila;Diaz, Marilyn;Aldon, Yoann;Bijl, Tom P. L.;Venkatayogi, Sravani;Beem, Joshua S. Martin;Newman, Amanda;Jiang, Chuancang;Lee, Wen-Hsin;Pater, Maarten;Burger, Judith A.;Breemen, Marielle J. van;Taeye, Steven W. de;Rantalainen, Kimmo;LaBranche, Celia;Saunders, Kevin O.;Montefiori, David;Ozorowski, Gabriel;Ward, Andrew B.;Crispin, Max;Moore, John P.;Klasse, Per Johan;Haynes, Barton F.;Wilson, Ian A.;Wiehe, Kevin;Verkoczy, Laurent;Sanders, Rogier W.
靶向广泛中和抗体（bNAb）的生殖系（gl-）前体被认为是HIV-1疫苗的重要策略。BNAb的VRC 01类是有吸引力的，因为它独特的基因签名。然而，VRC 01类bNAb通常需要广泛的体细胞超突变，包括罕见的插入和缺失。我们描述了一种BG 505 SOSIP三聚体，称为GT 1.2，以优化与gl-CH 31的结合，gl-CH 31是CH 30 -34 bNAb谱系的未突变的共同前体，其获得了大的CDRH 1插入。GT 1.2三聚体激活敲入小鼠中的gl-CH 31幼稚B细胞，并且B细胞应答可以通过选择的加强免疫原成熟以产生交叉反应性Ab应答。下一代B细胞测序揭示了对VRC 01类突变的选择，包括在与VRC 01类bNAb相同的位置插入CDRH 1和FWR 3中，以及CDRL 1缺失和/或甘氨酸取代以适应N276聚糖。这些结果为疫苗诱导的需要罕见插入和缺失的B细胞谱系的亲和力成熟提供了概念证明。生殖系靶向HIV-1 Env SOSIP GT 1.2激活小鼠模型中的bNA B前体B细胞显示VRC 01类成熟和多残基插入和缺失分离的VRC 01类mAb中和多种含N276聚糖的假病毒多残基插入是mAb中和所必需的bNAb的诱导对于保护性HIV-1疫苗是必需的，但目前的疫苗不能诱导足够的B细胞成熟。Caniels等人描述了一种免疫方案，其激发针对CD 4 b的中和抗体并分离具有类似于bNAb的罕见序列特征的单克隆抗体。
Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions. Germline-targeting HIV-1 Env SOSIP GT1.2 activates bNAb precursors in a mouse model B cells display VRC01-class maturation and multi-residue insertions and deletions Isolated VRC01-class mAbs neutralize multiple N276 glycan-containing pseudoviruses Multi-residue insertions are necessary for mAb neutralization The induction of bNAbs is essential for a protective HIV-1 vaccine, but current vaccines are unable to induce sufficient B cell maturation. Caniels et al. describe an immunization regimen that elicits neutralizing antibodies toward the CD4bs and isolates monoclonal antibodies with rare sequence features that resemble bNAbs.
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影响因子：
64.5
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.
通讯作者：
Schief, William R.
影响因子：
8.8
作者：
Torrents de la Peña A;Julien JP;de Taeye SW;Garces F;Guttman M;Ozorowski G;Pritchard LK;Behrens AJ;Go EP;Burger JA;Schermer EE;Sliepen K;Ketas TJ;Pugach P;Yasmeen A;Cottrell CA;Torres JL;Vavourakis CD;van Gils MJ;LaBranche C;Montefiori DC;Desaire H;Crispin M;Klasse PJ;Lee KK;Moore JP;Ward AB;Wilson IA;Sanders RW
通讯作者：
Sanders RW
HIV-1 疫苗开发中的挑战。
影响因子：
64.8
作者：
Barouch, Dan H.
通讯作者：
Barouch, Dan H.
DOI：
10.1107/s1744309110038212
发表时间：
2010-10-01
影响因子：
0.9
作者：
Elsliger, Marc-Andre;Deacon, Ashley M.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
影响因子：
64.5
作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
通讯作者：
Sanders RW