Kumar Sanjeev, Singh Swarandeep, Chatterjee Arnab, Bajpai Prashant, Sharma Shaifali, Katpara Sanket, Lodha Rakesh, Dutta Somnath, Luthra Kalpana
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India.
iScience. 2023 Aug 9;26(9):107579. doi: 10.1016/j.isci.2023.107579. eCollection 2023 Sep 15.
The structural and characteristic features of HIV-1 broadly neutralizing antibodies (bnAbs) from chronically infected pediatric donors are currently unknown. Herein, we characterized a heavy chain matured HIV-1 bnAb 44m, identified from a pediatric elite-neutralizer. Interestingly, in comparison to its wild-type AIIMS-P01 bnAb, 44m exhibited moderately higher level of somatic hypermutations of 15.2%. The 44m neutralized 79% of HIV-1 heterologous viruses (n = 58) tested, with a geometric mean IC titer of 0.36 μg/mL. The cryo-EM structure of 44m Fab in complex with fully cleaved glycosylated native-like BG505.SOSIP.664.T332N gp140 envelope trimer at 4.4 Å resolution revealed that 44m targets the V3-glycan N332-supersite and GDIR motif to neutralize HIV-1 with improved potency and breadth, plausibly attributed by a matured heavy chain as compared to that of wild-type AIIMS-P01. This study further improves our understanding on pediatric HIV-1 bnAbs and structural basis of broad HIV-1 neutralization by 44m may be useful blueprint for vaccine design in future.
来自慢性感染儿童供体的HIV-1广谱中和抗体（bnAbs）的结构和特征目前尚不清楚。在此，我们对一种从儿童精英中和者中鉴定出的重链成熟HIV-1 bnAb 44m进行了表征。有趣的是，与其野生型AIIMS-P01 bnAb相比，44m表现出15.2%的体细胞超突变水平略高。44m中和了79%的测试HIV-1异源病毒（n = 58），几何平均IC滴度为0.36 μg/mL。44m Fab与完全切割的糖基化天然样BG505.SOSIP.664.T332N gp140包膜三聚体复合物的冷冻电镜结构在4.4 Å分辨率下显示，44m靶向V3-聚糖N332超位点和GDIR基序，以提高效力和广度中和HIV-1，这可能归因于与野生型AIIMS-P01相比成熟的重链。这项研究进一步增进了我们对儿童HIV-1 bnAbs的理解，44m广泛中和HIV-1的结构基础可能为未来疫苗设计提供有用的蓝图。
