A VH1-69 antibody lineage from an infected Chinese donor potently neutralizes HIV-1 by targeting the V3 glycan supersite
A VH1-69 antibody lineage from an infected Chinese donor potently neutralizes HIV-1 by targeting the V3 glycan supersite
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DOI：
10.1126/sciadv.abb1328
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
Shao, Yiming
中科院分区：
文献类型：
--
作者：
Kumar, Sonu;Ju, Bin;Shao, Yiming
HIV-1包膜糖蛋白（Env）V3碱基周围的寡聚甘露糖斑块可被多种广泛中和抗体（bNAb）识别。本研究通过Env特异性单B细胞分选、结构和功能研究以及抗体和病毒库的纵向分析，研究了中国HIV-1感染者中bNA B对V3聚糖超位点的反应。分离出的单克隆抗体438-611和438-D5以中等宽度有效中和HIV-1，由V（H）1-69种系基因编码，并具有二硫键连接的长HCDR 3环。Env结合和未结合抗体的晶体结构揭示了重链介导的聚糖超位点识别，具有独特的方法角度和HCDR 3内二硫化物的关键作用。通过单基因组扩增/测序和N332超位点周围的聚糖突变来检查病毒逃逸的机制。我们的发现进一步强调了V3聚糖超位点作为基于Env的疫苗设计的突出靶标。
An oligomannose patch around the V3 base of HIV-1 envelope glycoprotein (Env) is recognized by multiple classes of broadly neutralizing antibodies (bNAbs). Here, we investigated the bNAb response to the V3 glycan supersite in an HIV-1-infected Chinese donor by Env-specific single B cell sorting, structural and functional studies, and longitudinal analysis of antibody and virus repertoires. Monoclonal antibodies 438-611 and 438-D5 were isolated that potently neutralize HIV-1 with moderate breadth, are encoded by the V(H)1-69 germline gene, and have a disulfide-linked long HCDR3 loop. Crystal structures of Env-bound and unbound antibodies revealed heavy chain-mediated recognition of the glycan supersite with a unique angle of approach and a critical role of the intra-HCDR3 disulfide. The mechanism of viral escape was examined via single-genome amplification/sequencing and glycan mutations around the N332 supersite. Our findings further emphasize the V3 glycan supersite as a prominent target for Env-based vaccine design.