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

作者：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.^*

来源：Immunity, 2018, 49(2): 301-+.

DOI：10.1016/j.immuni.2018.07.005

• BROADLY NEUTRALIZING ANTIBODY
• X-SER/THR SEQUON
• ANTIGENIC DETERMINANTS
• STRUCTURAL BASIS
• AMINO-ACID
• VACCINE DESIGN
• BINDING-SITE
• VIRUS
• GP120
• IMMUNOGENICITY

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 VRC01class 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 V-H 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.

• 出版日期2018-8-21