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

• Published in: Immunity (Cambridge, Mass.) Vol. 49; no. 2; pp. 301 - 311.e5
• Main Authors: Duan, Hongying, Chen, Xuejun, Boyington, Jeffrey C., Cheng, Cheng, Zhang, Yi, Jafari, Alexander J., Stephens, Tyler, Tsybovsky, Yaroslav, Kalyuzhniy, Oleksandr, Zhao, Peng, Menis, Sergey, Nason, Martha C., Normandin, Erica, Mukhamedova, Maryam, DeKosky, Brandon J., Wells, Lance, Schief, William R., Tian, Ming, Alt, Frederick W., Kwong, Peter D., Mascola, John R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2018; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; AIDS; AIDS Vaccines - immunology; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Binding sites; Binding Sites, Antibody - immunology; Broadly Neutralizing Antibodies; CD4 antigen; CD4 Antigens - immunology; CD4-binding site; Cell Line; Clinical trials; Crystal structure; eOD-GT8; Epitopes; Experiments; Female; Gene Knock-In Techniques; Glycan; glycan masking; Glycoproteins; HIV; HIV Antibodies - immunology; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV Infections - prevention & control; HIV-1; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune response; Immunoglobulin G; Immunoglobulin Heavy Chains - immunology; Immunoglobulins; Lymphocytes B; Male; Masking; Medical research; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutants; Mutation; N-glycans; Nanoparticles; neutralizing antibody; Polysaccharides; Polysaccharides - chemistry; Precursors; Priming; Proteins; single-cell sorting; Software; Statistical analysis; transgenic mouse; vaccination; Vaccines; VRC01; VRC01-class precursors; HIV-1; eOD-GT8; glycan masking; VRC01-class precursors; neutralizing antibody; VRC01; CD4-binding site; single-cell sorting; transgenic mouse; vaccination
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2018.07.005

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. [Display omitted] •Engineering N-linked glycans onto eOD-GT8 improves its immunogenic specificity•Added glycans mask binding to non-CD4bs antibodies but not VRC01-class antibodies•Glycan masking focuses B cell response to CD4bs in human VH1-2 mouse model•The strategy enhances induction of VRC01-class antibody precursors in mice 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.