Pathogens that manage to evade neutralization by the humoral immune system are often difficult vaccine targets. HIV-1 is one such pathogen. While the HIV-1 envelope (Env) is a primary target for antibodies elicited during infection, only a small minority of HIV-1-infected individuals elicit broadly neutralizing antibodies, and the bulk of humoral responses against HIV-1 consists of antibodies that do not neutralize - or that do so with limited breadth and/or potency. Understanding mechanisms of humoral evasion may therefore be critical to the development of an effective vaccine. We have been using atomic-level structural investigations, either through X-ray crystallography or cryo-EM microscopy, as our primary means for understanding Env mechanism of immune evasion. In 2014, we published the first full atomic-level structure of the prefusion closed HIV-1 Env trimer; this structure reveals gp41 conformational changes, location of sequence variation, and details of the glycan shield. In 2016, we published the crystal structure of a fully glycosylated Env trimer; this structure revealed how all antibodies that target the prefusion closed trimer must overcome glycan masking. We are now adding additional structural details, based on molecular dynamics studies, on smFRET studies, or on structures of additional functional intermediates.
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