Abstract
The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120–gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 Å resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120–gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.
Highlights
The recent identification of three broadly neutralizing antibodies against gp120–gp[41] interface epitopes has expanded the targetable surface on the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) trimer
The complementarity-determining regions (CDRs) of the two fragment antigen binding (Fab) are in very similar conformations with Ca root mean squared deviation of 0.58 Å (Fig. 1b) for the variable regions, suggesting that the two Fabs likely interact with Env in a similar manner
While alanine-scanning mutagenesis provided some clues about the location of the epitope, our cryo-Electron microscopy (EM) structure clearly revealed its location at the gp41–gp[41] inter-subunit interface on the pre-fusion conformation of the Env trimer
Summary
The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120–gp[41] interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. The majority of known bnAbs target one of four epitope clusters on the surface of Env that are often composed of both peptide and glycan components These sites include the receptor, or CD4, binding site (CD4bs)[3,4], the quaternary epitope surrounding the N160 glycan at the apex of the trimer[1,6,12,13], the high-mannose patch on the outer domain of gp[120] that includes the N332 glycan at the base of variable loop 3 (V3)[1,14,15,16] and the membrane-proximal external region (MPER) of gp[41]. The PGT151 and 35O22 epitopes, in particular, are highly dependent on the quaternary structure of the closed, pre-fusion form of Env[13,17,18,19]
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