Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env
Edgar A. Hodge,
Gajendra S. Naika,
Sally M. Kephart,
Adam Nguyen,
Richard Zhu,
Mark A. Benhaim,
Wenjin Guo,
John P. Moore,
Shiu-Lok Hu,
Rogier W. Sanders,
Kelly K. Lee
Affiliations
Edgar A. Hodge
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Gajendra S. Naika
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Sally M. Kephart
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Adam Nguyen
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; Biological Physics, Structure and Design Graduate Program, University of Washington, Seattle, WA 98195, USA
Richard Zhu
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Mark A. Benhaim
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Wenjin Guo
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
John P. Moore
Division of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
Shiu-Lok Hu
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA
Rogier W. Sanders
Division of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Kelly K. Lee
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; Biological Physics, Structure and Design Graduate Program, University of Washington, Seattle, WA 98195, USA; Corresponding author
Summary: 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.
