Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth.
Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth.
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DOI：
10.1016/j.immuni.2020.12.014
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发表时间：
2021-02-09
期刊：
影响因子：
32.4
通讯作者：
Mascola JR
中科院分区：
文献类型：
--
作者：
Chen X;Zhou T;Schmidt SD;Duan H;Cheng C;Chuang GY;Gu Y;Louder MK;Lin BC;Shen CH;Sheng Z;Zheng MX;Doria-Rose NA;Joyce MG;Shapiro L;Tian M;Alt FW;Kwong PD;Mascola JR
广泛中和抗体(BNAbs)的疫苗激发是HIV研究的一个关键目标。VRC01类bNAbs以HIV包膜三聚体上的CD4结合部位为靶点，需要广泛的体细胞超突变才能有效地中和。尽管取得了实质性的进展，但从未突变的前体开始的疫苗诱导的VRC01类抗体表现出有限的中和广度，特别是对大多数流通毒株上存在的携带多糖276的病毒。在这里，使用表达不同未突变的VRC01类抗体前体的免疫球蛋白人源化小鼠的顺序免疫，我们诱导了能够中和携带多糖276的病毒的血清反应，并分离出多个VRC01类bNAb谱系，其中包括208株面板上的两个50%宽度的VRC01类bNAbs。具有代表性的bNAbs的晶体结构显示了与已知的VRC01类bNAbs相同的识别模式。结构-功能研究进一步明确了关键突变，并将它们的诱导与特定的免疫联系起来。因此，VRC01类bNAbs可以通过从未突变的祖先到50%广度的顺序免疫来成熟，我们描述了诱导关键体细胞高突变的免疫原和方案。
Vaccine elicitation of broadly neutralizing antibodies (bnAbs) is a key HIV-research goal. The VRC01-class of bnAbs targets the CD4-binding site on the HIV-envelope trimer and requires extensive somatic hypermutation to neutralize effectively. Despite substantial progress, vaccine-induced VRC01-class antibodies starting from unmutated precursors have exhibited limited neutralization breadth, particularly against viruses bearing glycan276, present on most circulating strains. Here, using sequential immunization of immunoglobulin-humanized mice expressing diverse unmutated VRC01-class antibody precursors, we elicited serum responses capable of neutralizing viruses bearing glycan276 and isolated multiple lineages of VRC01-class bnAbs, including two with >50% breadth on a 208-strain panel. Crystal structures of representative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs. Structure-function studies further pinpointed key mutations and correlated their induction with specific immunizations. VRC01-class bnAbs can thus be matured by sequential immunization from unmutated ancestors to >50% breadth, and we delineate immunogens and regimens inducing key somatic hypermutation.
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影响因子：
82.9
作者：
Hessell AJ;Jaworski JP;Epson E;Matsuda K;Pandey S;Kahl C;Reed J;Sutton WF;Hammond KB;Cheever TA;Barnette PT;Legasse AW;Planer S;Stanton JJ;Pegu A;Chen X;Wang K;Siess D;Burke D;Park BS;Axthelm MK;Lewis A;Hirsch VM;Graham BS;Mascola JR;Sacha JB;Haigwood NL
通讯作者：
Haigwood NL
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：
--
作者：
Giudicelli, Veronique;Brochet, Xavier;Lefranc, Marie-Paule
通讯作者：
Lefranc, Marie-Paule
影响因子：
17.1
作者：
Pegu A;Yang ZY;Boyington JC;Wu L;Ko SY;Schmidt SD;McKee K;Kong WP;Shi W;Chen X;Todd JP;Letvin NL;Huang J;Nason MC;Hoxie JA;Kwong PD;Connors M;Rao SS;Mascola JR;Nabel GJ
通讯作者：
Nabel GJ
影响因子：
16.6
作者：
McGuire AT;Gray MD;Dosenovic P;Gitlin AD;Freund NT;Petersen J;Correnti C;Johnsen W;Kegel R;Stuart AB;Glenn J;Seaman MS;Schief WR;Strong RK;Nussenzweig MC;Stamatatos L
通讯作者：
Stamatatos L