Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2018-08, Vol.49 (2), p.301-311.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.