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

Author:

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
Author Address

Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA., Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Biostatistics Research Branch, Division of Clinical Research, NIAID, NIH, Bethesda, MD 20852, USA., Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA; Department of Chemical & Petroleum Engineering, The University of Kansas, Lawrence, KS 66045, USA; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Boston Children 39;s Hospital and Harvard Medical School, Boston, MA 02115, USA., Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.,

Abstract:

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. Published by Elsevier Inc.

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