The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Nat Immunol. 2024 Jun;25(6):1083-1096. doi: 10.1038/s41590-024-01844-7. Epub 2024 May 30.
Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.
目前,预防人体免疫缺陷病毒 1 (HIV-1) 的疫苗研究旨在引发广泛中和抗体 (bnAbs)。靶向膜近端外区 (MPER) 的 bnAbs,如 10E8,提供了异常广泛的中和作用,但有些是自身反应性的。在这里,我们生成了人源化 B 细胞抗原受体嵌合小鼠模型,以测试一系列针对种系的免疫原是否可以将 MPER 特异性前体引导至 bnAbs。我们发现,10E8 前体募集到生发中心 (GC) 需要对种系靶向免疫原具有最低亲和力,但由于高亲和力内源性 B 细胞竞争物的置换,MPER 前体在 GC 中的驻留时间很短。更高亲和力的种系靶向免疫原延长了 MPER 前体的 GC 驻留时间,但只有在 MPER-HuGL18 中观察到了强大的长期 GC 驻留和成熟,MPER-HuGL18 是一种能够在 GC 中与内源性 B 细胞竞争物缩小亲和力差距的 MPER 前体克隆型。因此,种系靶向免疫原可以诱导靶向 MPER 的抗体,而 GC 中的 B 细胞驻留可能受前体-竞争物亲和力差距的调节。
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