Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies

Summary The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a “β strand” interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
Graphical Abstract
Highlights • bnAb ACS202 penetrates the glycan shield to target the FP of HIV-1 Env gp41 • FP interacts with CDRH3 of ACS202 through a main-chain β strand interaction • bnAbs approach Env from diverse angles to target different dispositions of FP • FP-targeting bnAbs have varying tolerance to natural diversity in FP sequences
The HIV-1 Env fusion peptide (FP) is a site of vulnerability targeted by the immune system. Yuan et al. show that broadly neutralizing antibody ACS202 penetrates the Env glycan shield to target the FP. The diverse approach angles to the FP by different neutralizing antibodies provide insights for vaccine design.