Mechanisms Of Humoral Evasion

设法逃避体液免疫系统中和的病原体往往是难以接种疫苗的目标。HIV-1就是这样一种病原体。虽然HIV-1包膜（Env）是感染期间引发的抗体的主要靶标，但只有一小部分HIV-1感染者会引发广泛中和的抗体，而针对HIV-1的大部分体液反应由不能中和的抗体组成，或者是广度和/或效力有限的抗体。因此，了解体液逃避的机制可能对开发有效的疫苗至关重要。

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.