Structure-guided stabilization improves the ability of the HIV-1 gp41 hydrophobic pocket to elicit neutralizing antibodies.

Autor:	Bruun TUJ; Sarafan ChEM-H, Stanford University, Stanford, California, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA., Tang S; Sarafan ChEM-H, Stanford University, Stanford, California, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA., Erwin G; Sarafan ChEM-H, Stanford University, Stanford, California, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA., Deis L; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA., Fernandez D; Sarafan ChEM-H, Stanford University, Stanford, California, USA; Chem-H Macromolecular Structure Knowledge Center (MSKC), Stanford University, Stanford, California, USA., Kim PS; Sarafan ChEM-H, Stanford University, Stanford, California, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA; Chan Zuckerberg Biohub, San Francisco, California, USA. Electronic address: kimpeter@stanford.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Apr; Vol. 299 (4), pp. 103062. Date of Electronic Publication: 2023 Feb 24.
DOI:	10.1016/j.jbc.2023.103062
Abstrakt:	The hydrophobic pocket found in the N-heptad repeat (NHR) region of HIV-1 gp41 is a highly conserved epitope that is the target of various HIV-1-neutralizing monoclonal antibodies. Although the high conservation of the pocket makes it an attractive vaccine candidate, it has been challenging to elicit potent anti-NHR antibodies via immunization. Here, we solved a high-resolution structure of the NHR mimetic IQN17, and, consistent with previous ligand-bound gp41 pocket structures, we observed remarkable conformational plasticity of the pocket. The high malleability of this pocket led us to test whether we could improve the immunogenicity of the gp41 pocket by stabilizing its conformation. We show that the addition of five amino acids at the C terminus of IQN17, to generate IQN22, introduces a stabilizing salt bridge at the base of the peptide that rigidifies the pocket. Mice immunized with IQN22 elicited higher avidity antibodies against the gp41 pocket and a more potent, albeit still weak, neutralizing response against HIV-1 compared with IQN17. Stabilized epitope-focused immunogens could serve as the basis for future HIV-1 fusion-inhibiting vaccines. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu