Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.
Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden.
J Immunol. 2021 Mar 1;206(5):999-1012. doi: 10.4049/jimmunol.2001082. Epub 2021 Jan 20.
Vaccine efforts to combat HIV are challenged by the global diversity of viral strains and shielding of neutralization epitopes on the viral envelope glycoprotein trimer. Even so, the isolation of broadly neutralizing Abs from infected individuals suggests the potential for eliciting protective Abs through vaccination. This study reports a panel of 58 mAbs cloned from a rhesus macaque () immunized with envelope glycoprotein immunogens curated from an HIV-1 clade C-infected volunteer. Twenty mAbs showed neutralizing activity, and the strongest neutralizer displayed 92% breadth with a median IC of 1.35 μg/ml against a 13-virus panel. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C) with others targeting the V3 ladle orientation (V3L), the CD4 binding site (CD4bs), C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of Ab-dependent cellular cytotoxicity, but did not predict the degree of Ab-dependent cellular phagocytosis. Using an individualized germline gene database, mAbs were traced to 23 of 72 functional IgHV alleles. Neutralizing V3C Abs displayed minimal nucleotide somatic hypermutation in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. Overall, this study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of the human donor's humoral immune response through nonhuman primate vaccination.
针对 HIV 的疫苗接种工作面临着全球病毒株多样性的挑战，以及病毒包膜糖蛋白三聚体上中和表位的屏蔽。即便如此，从感染个体中分离出广泛中和抗体表明，通过接种疫苗引发保护性抗体是有可能的。本研究报告了一组 58 种 mAb，它们是从恒河猴（Macaca mulatta）中克隆出来的，这些恒河猴用从一名 HIV-1 谱系 C 感染者志愿者中筛选出的包膜糖蛋白免疫原进行免疫。20 种 mAb 显示出中和活性，最强的中和剂对 13 种病毒的中和率为 92%，IC 的中位数为 1.35 μg/ml。中和 mAb 主要靶向 V3 区域的线性表位，呈“摇篮”构象（V3C），而其他 mAb 则靶向 V3 勺状构象（V3L）、CD4 结合位点（CD4bs）、C1、C4 或 gp41。非中和 mAb 结合 C1、C5 或未确定的构象表位。中和效力与感染的恒河猴脾细胞的结合程度以及 Ab 依赖性细胞毒性的水平密切相关，但不能预测 Ab 依赖性细胞吞噬的程度。使用个体化的种系基因数据库，将 mAb 追溯到 72 个功能性 IgHV 基因座中的 23 个。针对 V3C 的中和 mAb 在 H 链 V 区的核苷酸体细胞超突变很少（3.77%），这表明实现谱系内中和广度需要的亲和力成熟相对较少。总的来说，本研究强调了疫苗诱导的 2 级中和 V3 Abs 的多功能性，并通过非人类灵长类动物接种证明了对人类供体体液免疫反应的部分重现。
