Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env

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. Weshow that significant differences in epitope order are observed across most sites targeted by broadly neutralizing antibodies. Wealso 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.

Automated summary

Using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), the study mapped the local dynamics of native-like Env SOSIP trimers from diverse isolates. The results showed significant differences in epitope order across most sites targeted by broadly neutralizing antibodies, and isolate-dependent conformational switching occurring over a broad range of timescales. Furthermore, hyper-stabilizing mutations that dampen dynamics in some isolates had little effect on others.