Rationally designed carbohydrate-occluded epitopes elicit HIV-1 Env-specific antibodies.

Nature Communications
Cheng ZhuNikolay V Dokholyan

Abstract

An array of carbohydrates masks the HIV-1 surface protein Env, contributing to the evasion of humoral immunity. In most HIV-1 isolates 'glycan holes' occur due to natural sequence variation, potentially revealing the underlying protein surface to the immune system. Here we computationally design epitopes that mimic such surface features (carbohydrate-occluded neutralization epitopes or CONE) of Env through 'epitope transplantation', in which the target region is presented on a carrier protein scaffold with preserved structural properties. Scaffolds displaying the four CONEs are examined for structure and immunogenicity. Crystal structures of two designed proteins reflect the computational models and accurately mimic the native conformations of CONEs. The sera from rabbits immunized with several CONE immunogens display Env binding activity. Our method determines essential structural elements for targets of protective antibodies. The ability to design immunogens with high mimicry to viral proteins also makes possible the exploration of new templates for vaccine development.

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Citations

Jun 12, 2020·Emerging Microbes & Infections·Yuezhi LinXiaojun Wang
Nov 25, 2020·Proteins·Dong Yan ZhangNikolay V Dokholyan
Feb 7, 2021·Cancer Immunology Research·Elisa LandoniGianpietro Dotti
Apr 2, 2021·PLoS Computational Biology·Mateusz SikoraGerhard Hummer

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Datasets Mentioned

BETA
KC894098

Methods Mentioned

BETA
glycosylation
size
NMR
circular dichroism
nuclear magnetic resonance
enzyme-linked immunosorbent assay
ELISA
size exclusion chromatography
column chromatography
X-ray

Software Mentioned

Gatan Microscopy Suite
MCSG Crystallization
Erebus
NanoSight
NMRPipe
BioEdit
Sparky
Eris
MARS
Naccess

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