Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies
| Autor: | Peter D. Kwong, William R. Schief, Peng Zhao, Xuejun Chen, Yaroslav Tsybovsky, Cheng Cheng, Maryam Mukhamedova, Lance Wells, Oleksandr Kalyuzhniy, J.C. Boyington, Brandon J. DeKosky, Frederick W. Alt, Tyler Stephens, Ming Tian, Erica Normandin, Hongying Duan, John R. Mascola, Yi Zhang, Martha Nason, Alexander J. Jafari, Sergey Menis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Glycan Immunogen Immunology HIV Infections Mice Transgenic HIV Antibodies HIV Envelope Protein gp120 Immunoglobulin G Epitope Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Polysaccharides Immunology and Allergy Animals Humans Gene Knock-In Techniques Binding site Neutralizing antibody AIDS Vaccines biology Antibodies Monoclonal Antibodies Neutralizing Cell biology Mice Inbred C57BL 030104 developmental biology Infectious Diseases CD4 Antigens biology.protein HIV-1 Immunoglobulin heavy chain Female Binding Sites Antibody Antibody Immunoglobulin Heavy Chains 030217 neurology & neurosurgery Broadly Neutralizing Antibodies |
| Zdroj: | Immunity. 49(2) |
| ISSN: | 1097-4180 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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