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Binding of Neutralizing Antibodies Results in Distinct Quaternary Conformations of Trimeric HIV-1 Envelope Glycoproteins.
The HIV surface glycoprotein, Env, initiates HIV infection by binding to cell-surface CD4 and a co-receptor molecule on T cells. Understanding the interactions of these molecules with native, trimeric Env is crucial for effective vaccine design. Using cryo-electron tomography of intact HIV, we show that binding to either the co-receptor mimic 17b or soluble CD4 is sufficient for formation of an open quaternary conformation of Env. In contrast, binding of the broadly neutralizing, CD4-binding-site antibody, VRC01, locks Env in the native, closed conformation, preventing 17b binding and formation of the open Env conformation. The CD4-binding-site antibody, b12, requires a partial opening in the quaternary structure of Env and cannot bind in the conformation that binds to the VRC antibodies due to steric clashes. Our results show that, despite general similarities in regions of the HIV-1 gp120 polypeptide that contact CD4, VRC01 and b12, important differences exist in the quaternary structures of these complexes. These findings shed new mechanistic insight into the HIV entry process and potentially explain differences in the neutralizing breadth and potency of antibodies with similar specificities.