Glycan-Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies

By Hongying Duan, Xuejun Chen, J. Boyington, Cheng Cheng, Yi Zhang, Alexander J. Jafari, T. Stephens, Y. Tsybovsky, Oleksandr Kalyuzhniy, Peng Zhao and 11 more. 2018

140 citations recorded by the source corpus.

SUMMARY An important class of HIV‐1 broadly neutralizing antibodies, termed the VRC01 class, targets the conserved CD4‐binding site (CD4bs) of the envelope glycoprotein (Env). An engineered Env outer domain (OD) eOD‐GT8 60‐mer nanoparticle has been developed as a priming immunogen for eliciting VRC01‐class precursors and is planned for clinical trials. However, a substantial portion of eOD‐GT8‐elicited antibodies target non‐CD4bs epitopes, potentially limiting its efficacy. We introduced N‐linked glycans into non‐CD4bs surfaces of eOD‐GT8 to mask irrelevant epitopes and evaluated these mutants in a mouse model that expressed diverse immunoglobulin heavy chains containing human IGHV1‐2*02, the germline VRC01 VH segment. Compared to the parental eOD‐GT8, a mutant with five added glycans stimulated significantly higher proportions of CD4bs‐specific serum responses and CD4bs‐specific immunoglobulin G+ B cells including VRC01‐class precursors. These results demonstrate that glycan masking can limit elicitation of off‐target antibodies and focus immune responses to the CD4bs, a major target of HIV‐1 vaccine design. Graphical Abstract Figure. No caption available. HighlightsEngineering N‐linked glycans onto eOD‐GT8 improves its immunogenic specificityAdded glycans mask binding to non‐CD4bs antibodies but not VRC01‐class antibodiesGlycan masking focuses B cell response to CD4bs in human VH1‐2 mouse modelThe strategy enhances induction of VRC01‐class antibody precursors in mice &NA; A substantial portion of the engineered HIV gp120 immunogen eOD‐GT8‐elicited antibodies target non‐CD4 binding site (bs) epitopes, potentially limiting its efficacy. Duan et al. used N‐linked glycans to mask epitopes outside the CD4bs of eOD‐GT8, leading to enhanced elicitation of CD4bs antibodies, including VRC01‐class precursors, and reduced off‐target antibody responses in a human VH1‐2 mouse model.

Subfields: Immunology, Radiology, Nuclear Medicine and Imaging, Virology

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In Immunology

1. F. Sallusto
2. A. Lanzavecchia
3. Rafi Ahmed
4. Bali Pulendran
5. V. Schirrmacher

In Radiology, Nuclear Medicine and Imaging

1. Neil P. King
2. M. Kanekiyo
3. Daniel Ellis
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5. David Baker
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7. Frances H. Arnold

In Virology

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2. F. Sallusto
3. A. Lanzavecchia

Citations in the corpus

• Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, background): “In all cases, immunogenicity of the antigen was increasedbymultivalent presentation, and in somecases, an epitope-focusingeffectwasobserved inwhichpotent neutralizing epitopeswere preferentially targeted (Duan et al., 2018; Kanekiyo et al., 2015; Yassine et al., 2015).”
• Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding (2020, unknown): “Second, our maps show which mutations can be introduced into the RBD without disrupting key biochemical phenotypes, thereby opening the door to resurfacing immunogens to focus antibodies on specific epitopes (Duan et al., 2018; Eggink et al., 2014; Jardine et al., 2016; Kulp et al., 2017; Weidenbach”
• New Vaccine Design and Delivery Technologies (2019, background): “In some cases, self-assembling scaffolds were successfully combined with antigens designed to focus the response on specific epitopes and therefore improve neutralization potency or breadth [33, 44, 48] .”
• Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, unknown): “Second, our maps show which mutations can be introduced into the RBD without disrupting key biochemical phenotypes, thereby opening the door to resurfacing immunogens to focus antibodies on specific epitopes (Duan et al., 2018; Eggink et al., 2014; Jardine et al., 2016; Kulp et al., 2017; Weidenbach”