Mechanisms Of Humoral Evasion

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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-electron microscopy (EM), as our primary means for understanding Env mechanism of immune evasion. In 2012, we published the structure of the V1V2 region; this structure revealed the domain structure of the last unknown portion of the gp120 glycoprotein; in 2014, we published the first full atomic-level structure of the prefusion-closed HIV-1 Env trimer; this structure revealed gp41 conformational changes, location of sequence variation, and details of the glycan shield; in 2016, we published the structure of a fully glycosylated Env trimer; this structure revealed how all antibodies that target the prefusion closed trimer must overcome glycan masking; and in 2020, we co-published the cryo-electron tomogram of the Env trimer on virions. We are now adding additional structural details, based on molecular dynamics studies, on smFRET studies, or on structures of additional functional intermediates. In addition to HIV-1 Env trimer, we are also using atomic-level structural investigations to determine how other pathogens, including malaria, lassa virus or the recently emerged SARS-CoV-2, evade the humoral immune response. Some of these investigations involve strucutral investigations, whereas others involve the dissemination of proteins into their domains, and the mapping of immune responses to those domains.