HIV-1 Env is a primary target for antibodies elicited during infection. Although a small number of infected individuals elicit broadly neutralizing antibodies, the bulk of humoral response consists of antibodies that do not neutralize or do so with limited breadth and effect protection through Fc receptor-dependent processes, such as antibody-dependent cellular cytotoxicity (ADCC). We are using atomic-level structural investigations, either through X-ray crystallography or cryo-EM microscopy, as the 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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