@article{f7a4587ed70845ed904ce5c8d95fb29a,
title = "Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env",
abstract = "The envelope glycoprotein (Env) is the sole target for neutralizing antibodies against HIV and the most rapidly evolving, variable part of the virus. High-resolution structures of Env trimers captured in the pre-fusion, closed conformation have revealed a high degree of structural similarity across diverse isolates. Biophysical data, however, indicate that Env is highly dynamic, and the level of dynamics and conformational sampling is believed to vary dramatically between HIV isolates. Dynamic differences likely influence neutralization sensitivity, receptor activation, and overall trimer stability. Here, using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), we have mapped local dynamics across native-like Env SOSIP trimers from diverse isolates. We show that significant differences in epitope order are observed across most sites targeted by broadly neutralizing antibodies. We also observe isolate-dependent conformational switching that occurs over a broad range of timescales. Lastly, we report that hyper-stabilizing mutations that dampen dynamics in some isolates have little effect on others.",
keywords = "Immunology, Microbiology, Structural biology",
author = "Hodge, {Edgar A.} and Naika, {Gajendra S.} and Kephart, {Sally M.} and Adam Nguyen and Richard Zhu and Benhaim, {Mark A.} and Wenjin Guo and Moore, {John P.} and Shiu-Lok Hu and Sanders, {Rogier W.} and Lee, {Kelly K.}",
note = "Funding Information: We thank Dr. Susan Zolla-Pazner for generously providing the IgG mAbs 3074, 3869, 447-52D, 2158, and 830A. VRC01 and PG16 were obtained through the NIH AIDS Research and Reference Reagent Program. We also thank Dr. James A. Williams for assistance with BLI experiments, Dr. Klaus N. Lovendahl for insightful discussions, Dr. Miklos Guttman and Rick Harkewicz for assistance with HDX instrumentation, and the University of Washington's Proteomics Resource for technical support (UWPR95794). This study was supported by the Bill & Melinda Gates Foundation grant (OPP1126258) and NIH/NIAID grant R01 AI140868 to K.K.L. and NIH/NIAID grant R01 AI129673 to S.H.L. This work was also supported by the Netherlands Organization for Scientific Research (NWO) Vici grant (to R.W.S.); Bill & Melinda Gates Foundation grant INV-002022 (to R.W.S.), HIVRAD grant P01 AI 110657 (to J.P.M. and R.W.S.) R01 AI 36082 (to J.P.M.). Conceptualization: K.K.L, E.A.H; writing, E.A.H and K.K.L; writing review, M.A.B, R.W.S.; formal analysis, E.A.H. S.M.K.; SOSIP purification and characterization, G.S.N, E.A.H. A.N. W.G. R.Z.; IgG purification, E.A.H.; HDX-MS, E.A.H. S.M.K.; BLI, E.A.H.; glycoprofiling, E.A.H.; resources, R.W.S. S.L.H. and J.P.M.; funding acquisition, K.K.L. R.W.S. J.P.M. and S.L.H. The authors declare no competing interests. Funding Information: We thank Dr. Susan Zolla-Pazner for generously providing the IgG mAbs 3074, 3869, 447-52D, 2158, and 830A. VRC01 and PG16 were obtained through the NIH AIDS Research and Reference Reagent Program. We also thank Dr. James A. Williams for assistance with BLI experiments, Dr. Klaus N. Lovendahl for insightful discussions, Dr. Miklos Guttman and Rick Harkewicz for assistance with HDX instrumentation, and the University of Washington{\textquoteright}s Proteomics Resource for technical support (UWPR95794). This study was supported by the Bill & Melinda Gates Foundation grant ( OPP1126258 ) and NIH / NIAID grant R01 AI140868 to K.K.L., and NIH / NIAID grant R01 AI129673 to S.H.L. This work was also supported by the Netherlands Organization for Scientific Research ( NWO ) Vici grant (to R.W.S.); Bill & Melinda Gates Foundation grant INV-002022 (to R.W.S.), HIVRAD grant P01 AI 110657 (to J.P.M. and R.W.S.) R01 AI 36082 (to J.P.M.). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jun,
day = "17",
doi = "https://doi.org/10.1016/j.isci.2022.104449",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "6",
}