Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Peter D. Kwong
{"title":"在以融合肽为前体的 SHIV 感染猕猴体内发挥强效、广泛的 HIV-1 中和作用","authors":"Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Peter D. Kwong","doi":"10.1016/j.cell.2024.10.003","DOIUrl":null,"url":null,"abstract":"An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID<sub>50</sub>] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC<sub>50</sub>] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide <em>in vivo</em> molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"9 1","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques\",\"authors\":\"Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Peter D. Kwong\",\"doi\":\"10.1016/j.cell.2024.10.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID<sub>50</sub>] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC<sub>50</sub>] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide <em>in vivo</em> molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.\",\"PeriodicalId\":45,\"journal\":{\"name\":\"Journal of Chemical Theory and Computation\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-10-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Theory and Computation\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cell.2024.10.003\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Theory and Computation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2024.10.003","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques
An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID50] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC50] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.
期刊介绍:
The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.