气候变化领域集成服务门户(CCPortal): Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody

CCPortal

DOI	10.1073/pnas.2011653118
	Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody
	Madan B.; Zhang B.; Xu K.; Chao C.W.; O’Dell S.; Wolfe J.R.; Chuang G.-Y.; Fahad A.S.; Geng H.; Kong R.; Louder M.K.; Nguyen T.D.; Rawi R.; Schön A.; Sheng Z.; Nimrania R.; Wang Y.; Zhou T.; Lin B.C.; Doria-Rose N.A.; Shapiro L.; Kwong P.D.; DeKosky B.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti–HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Broadly neutralizing antibodies; Fusion peptide; HIV-1 vaccines; Somatic hypermutation; Yeast display
语种	英语
scopus关键词	Human immunodeficiency virus env protein; Human immunodeficiency virus vaccine; neutralizing antibody; Article; binding affinity; controlled study; gene mutation; genetic screening; human; human cell; Human immunodeficiency virus 1; Human immunodeficiency virus infection; in vivo study; molecular dynamics; priority journal; protein binding; signal transduction; site-saturation mutagenesis; somatic hypermutation; thermostability
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180386
作者单位	Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66045, United States; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, United States; Department of Biology, John Hopkins University, Baltimore, MD 21218, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, United States; Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY 10032, United States; Department of Chemical Engineering, The University of Kansas, Lawrence, KS 66045, United States
推荐引用方式 GB/T 7714	Madan B.,Zhang B.,Xu K.,et al. Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody[J],2021,118(10).
APA	Madan B..,Zhang B..,Xu K..,Chao C.W..,O’Dell S..,...&DeKosky B.J..(2021).Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Madan B.,et al."Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).