@article{b6a6958cfec94f71ad06978eeacab929,
title = "VSV-Displayed HIV-1 Envelope Identifies Broadly Neutralizing Antibodies Class-Switched to IgG and IgA",
abstract = "The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214. Donor B cell receptor (BCR) repertoires identified two bNAb lineages, M4008_N1 and M1214_N1, that class-switched to immunoglobulin G (IgG) and IgA. Variants of these bNAbs reconstituted as IgA demonstrated broadly neutralizing activity, and the IgA fraction of M1214 plasma conferred neutralization. M4008_N1 epitope mapping revealed a glycan-independent V3 epitope conferring tier 2 virus neutralization. A 4.86-{\AA}-resolution cryogenic electron microscopy (cryo-EM) structure of M1214_N1 complexed with CH505 SOSIP revealed another elongated epitope, the V2V5 corridor, extending from V2 to V5. Overall, the VSVENV probe identified bNAb lineages with neutralizing IgG and IgA members targeting distinct sites of HIV-1 Env vulnerability.",
keywords = "Env immunogen design, HIV vaccine, IgG to IgA, V2V5 corridor, antibody class-switch, broadly neutralizing antibody, cryo-EM",
author = "Manxue Jia and Liberatore, {Rachel A.} and Yicheng Guo and Chan, {Kun Wei} and Ruimin Pan and Hong Lu and Eric Waltari and Eva Mittler and Kartik Chandran and Andr{\'e}s Finzi and Kaufmann, {Daniel E.} and Seaman, {Michael S.} and Ho, {David D.} and Lawrence Shapiro and Zizhang Sheng and Kong, {Xiang Peng} and Bieniasz, {Paul D.} and Xueling Wu",
note = "Funding Information: We thank the participants in the Montreal HIV-1 infection study Cohort and Mario Legault for Cohort coordination. We also thank Dr. Zheng Liu for help with cryo-EM data collections and Dr. Xunqing Jiang for technical assistance. Financial support for this study was provided by the National Institutes of Health (NIH) grants R01 AI122953 to X.W. R37 AI64003 to P.D.B. P01 AI100151 and R01 AI145655 to X.-P.K. R21 AI138024 to Z.S. and R01 AI134824 to K.C.; by the National Center for Advancing Translational Sciences, NIH, grant UL1TR001866 through The Rockefeller University; and by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant OPP1146996 to M.S.S. A.F. is recipient of a Canada Research Chair. D.E.K is recipient of a FRQS Merit Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.J. R.A.L. P.D.B. and X.W. conceived and designed the study. M.J. R.A.L. Y.G. K.-W.C. R.P. H.L. and E.W. conducted experiments and analyzed data. E.M. K.C. A.F. D.E.K. M.S.S. and D.D.H. contributed critical resources and reagents. L.S. Z.S. and X.-P.K. supervised bioinformatics and structural analyses. L.S. Z.S. X.-P.K. P.D.B. and X.W. wrote the manuscript, on which all authors commented. The authors declare no competing interests. Funding Information: We thank the participants in the Montreal HIV-1 infection study Cohort and Mario Legault for Cohort coordination. We also thank Dr. Zheng Liu for help with cryo-EM data collections and Dr. Xunqing Jiang for technical assistance. Financial support for this study was provided by the National Institutes of Health (NIH) grants R01 AI122953 to X.W., R37 AI64003 to P.D.B., P01 AI100151 and R01 AI145655 to X.-P.K., R21 AI138024 to Z.S., and R01 AI134824 to K.C.; by the National Center for Advancing Translational Sciences , NIH , grant UL1TR001866 through The Rockefeller University ; and by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant OPP1146996 to M.S.S. A.F. is recipient of a Canada Research Chair. D.E.K is recipient of a FRQS Merit Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = jun,
day = "10",
doi = "10.1016/j.chom.2020.03.024",
language = "English (US)",
volume = "27",
pages = "963--975.e5",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "6",
}
