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Antigenicity and immunogenicity of HIV-1 gp140 with different combinations of glycan mutation and V1/V2 region or V3 crown deletion

Fu, M; Hu, K; Hu, H; Ni, F; Du, T; Shattock, R; Hu, Q (2019) Antigenicity and immunogenicity of HIV-1 gp140 with different combinations of glycan mutation and V1/V2 region or V3 crown deletion. VACCINE, 37 (51). pp. 7501-7508. ISSN 0264-410X https://doi.org/10.1016/j.vaccine.2019.09.073
SGUL Authors: Hu, Qinxue

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Abstract

The carbohydrate moieties on HIV-1 envelope glycoprotein (Env) act as shields to mask conserved neutralizing epitopes, while the hyperimmunogenic variable regions are immunodominant in inducing non-neutralizing antibodies, representing the major challenge for using Env as a vaccine candidate to induce broadly neutralizing antibodies (bNAbs). In this study, we designed a series of HIV-1 gp140 constructs with the removal of N276/N463 glycans, deletion of the V1/V2 region and the V3 crown, alone or in combination. We first demonstrated that all the constructs had a comparable level of expression and were mainly expressed as trimers. Following purification of gp140s from mammalian cells, we measured their binding to bNAbs and non-NAbs in vitro and capability in inducing bNAbs in vivo. Antibody binding assay showed that removal of N276/N463 glycans together with the deletion of V1/V2 region enhanced the binding of gp140s to CD4-binding site-targeting bNAbs VRC01 and 3BNC117, and CD4-induced epitopes-targeting non-NAbs A32, 17b and F425 A1g8, whereas further deletion of V3 crown in the gp140 mutants demonstrated slightly compromised binding capability to these Abs. Immunogenicity study showed that the above mutations did not lead to the induction of a higher Env-specific IgG response via either DNA-DNA or DNA-protein prime-boost strategies in mice, while neutralization assay did not show an apparent difference between wild type and mutated gp140s. Taken together, our results indicate that removal of glycans at N276/N463 and deletion of the V1/V2 region can expose the CD4-binding site and CD4-induced epitopes, but such exposure alone appears incapable of enhancing the induction of bNAbs in mice, informing that additional modification or/and immunization strategies are needed. In addition, the strategies which we established for producing gp140 proteins and for analyzing the antigenicity and immunogenicity of gp140 provide useful means for further vaccine design and assessment.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: 06 Biological Sciences, 07 Agricultural And Veterinary Sciences, 11 Medical And Health Sciences, Virology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: VACCINE
ISSN: 0264-410X
Dates:
DateEvent
3 December 2019Published
26 September 2019Published Online
20 September 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
2018ZX10301406-002National Mega-Projects against Infectious DiseasesUNSPECIFIED
2018ZX10301405-003National Mega-Projects against Infectious DiseasesUNSPECIFIED
81772192National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
URI: https://openaccess.sgul.ac.uk/id/eprint/111250
Publisher's version: https://doi.org/10.1016/j.vaccine.2019.09.073

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