Alpaca-derived nanobody targeting the hydrophobic pocket of the HIV-1 gp41 NHR broadly neutralizes HIV-1 by blocking six-helix bundle formation

Lujia Sun; Bo Chen; Xianbo Liu; Yun Zhu; Guangxu Zhang; Xiaoxing Liang; Lixiao Xing; Wei Xu; Shibo Jiang; Xinling Wang

Current Research in Microbial Sciences (Jan 2024)

Alpaca-derived nanobody targeting the hydrophobic pocket of the HIV-1 gp41 NHR broadly neutralizes HIV-1 by blocking six-helix bundle formation

Lujia Sun,
Bo Chen,
Xianbo Liu,
Yun Zhu,
Guangxu Zhang,
Xiaoxing Liang,
Lixiao Xing,
Wei Xu,
Shibo Jiang,
Xinling Wang

Affiliations

Lujia Sun: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China
Bo Chen: Chengdu NBbiolab. CO., LTD, SME Incubation Park, 319 Qingpi Avenue, Chengdu, China
Xianbo Liu: Chengdu NBbiolab. CO., LTD, SME Incubation Park, 319 Qingpi Avenue, Chengdu, China
Yun Zhu: National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Guangxu Zhang: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China
Xiaoxing Liang: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China
Lixiao Xing: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China
Wei Xu: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China
Shibo Jiang: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China; Corresponding authors.
Xinling Wang: Shanghai Institute of Infectious Disease and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China; Corresponding authors.

Journal volume & issue: Vol. 7
p. 100263

Abstract

Read online

The highly conserved hydrophobic pocket region of HIV-1 gp41 NHR triple-stranded coiled coil is crucial for the binding of CHR to NHR to form a six-helix bundle (6-HB). This pocket is only exposed instantaneously during fusion, making it an ideal target for antibody drug design. However, IgG molecule is too big to enter the pocket during the fusion process. Therefore, to overcome the steric hindrance and kinetic obstacles caused by the formation of gp41 pre-hairpin fusion intermediate, we obtained nanobodies (Nbs) targeting NHR by immunizing alpaca with an NHR-trimer mimic. Specifically, we identified a Nb, Nb-172, that exhibited potent and broadly neutralizing activity against HIV-1 pseudoviruses, HIV-1 primary isolates, and T20-resistant HIV-1 strains. In addition, the combinatorial use of mD1.22 and Nb-172 exhibited synergism in inhibiting HIV-1 infection inactivating cell-free virions. Nb-172 can competitively bind to the hydrophobic pocket of gp41 NHR to inhibit 6-HB formation. These findings suggest that Nb-172 merits further investigation as a potential therapeutic for HIV-1 infection.

Published in Current Research in Microbial Sciences

ISSN: 2666-5174 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Microbiology; Science: Biology (General): Genetics
Website: https://www.journals.elsevier.com/current-research-in-microbial-sciences

About the journal

Abstract

Keywords