Ability of nucleoside-modified mRNA to encode HIV-1 envelope trimer nanoparticles.
Ability of nucleoside-modified mRNA to encode HIV-1 envelope trimer nanoparticles.
复制标题
核苷修饰的 mRNA 编码 HIV-1 包膜三聚体纳米颗粒的能力。
DOI：
10.1101/2021.08.09.455714
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Venkatayogi,Sr
中科院分区：
文献类型：
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作者：
Mu,Zekun;Wiehe,Kevin;Saunders,KevinO;Henderson,Rory;Cain,DerekW;Parks,Robert;Martik,Diana;Mansouri,Katayoun;Edwards,RobertJ;Newman,Amanda;Lu,Xiaozhi;Xia,Shi-Mao;Bonsignori,Mattia;Montefiori,David;Han,Qifeng;Venkatayogi,Sr
脂质纳米粒中核苷修饰的mRNA（mRNA-LNP）作为COVID-19疫苗的成功预示着疫苗开发的新时代。对于HIV-1，与单独的三聚体相比，多价包膜（Env）三聚体蛋白纳米颗粒是用于引发广泛中和抗体（bnAb）B细胞谱系的上级免疫原。复合多价纳米颗粒免疫原与mRNA的成功表达尚未得到证实。在这里，我们表明mRNA可以编码铁蛋白纳米颗粒上的抗原性Env三聚体，其启动bnAb前体B细胞扩增并在bnAb前体VH + VL敲入小鼠中诱导血清自体2级中和活性。下一代测序证实获得了关键突变，并分离出了中和异源HIV-1分离株的单克隆抗体。因此，mRNA-LNP可以编码复杂的免疫原，并可用于设计用于HIV-1疫苗开发的生殖系靶向和连续加强免疫原。
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared to trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next generation sequencing demonstrated acquisition of critical mutations, and monoclonal antibodies that neutralized heterologous HIV-1 isolates were isolated. Thus, mRNA-LNP can encode complex immunogens and are of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.