Louise Scharf, Haoqing Wang, Han Gao, Songye Chen, Alasdair W. McDowall, Pamela J. Bjorkman
Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env
Highlights
- •3.58 Å structure of 8ANC195-Env trimer defines the gp120-gp41 site of HIV vulnerability
- •EM structure shows 8ANC195 binds Env trimer in CD4-bound partially open state
- •8ANC195 partially reverses CD4-induced open Env conformation
- •Binding closed and open Env suggests neutralization of free and cell-bound virus
Summary
The HIV-1 envelope (Env) spike contains limited epitopes for broadly neutralizing antibodies (bNAbs); thus, most neutralizing antibodies are strain specific. The 8ANC195 epitope, defined by crystal and electron microscopy (EM) structures of bNAb 8ANC195 complexed with monomeric gp120 and trimeric Env, respectively, spans the gp120 and gp41 Env subunits. To investigate 8ANC195’s gp41 epitope at higher resolution, we solved a 3.58 Å crystal structure of 8ANC195 complexed with fully glycosylated Env trimer, revealing 8ANC195 insertion into a glycan shield gap to contact gp120 and gp41 glycans and protein residues. To determine whether 8ANC195 recognizes the CD4-bound open Env conformation that leads to co-receptor binding and fusion, one of several known conformations of virion-associated Env, we solved EM structures of an Env/CD4/CD4-induced antibody/8ANC195 complex. 8ANC195 binding partially closed the CD4-bound trimer, confirming structural plasticity of Env by revealing a previously unseen conformation. 8ANC195’s ability to bind different Env conformations suggests advantages for potential therapeutic applications.
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This abstract was originally published on Cell on 10th September 2015 and re-published with permission.
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