Structural analysis of a novel rabbit monoclonal antibody R53 targeting an epitope in HIV-1 gp120 C4 region critical for receptor and co-receptor binding

• Published in: Emerging microbes & infections 2015-07, Vol.4 (1), p.1-8
• Main Authors: Pan, Ruimin, Chen, Yuxin, Vaine, Michael, Hu, Guangnan, Wang, Shixia, Lu, Shan, Kong, Xiang-Peng
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; BASIC BIOLOGICAL SCIENCES; Binding Sites, Antibody - immunology; Binding, Competitive; CD4; CD4 Antigens - immunology; CD4 Antigens - metabolism; Crystallization; Env; Epitopes - chemistry; Epitopes - immunology; Epitopes - metabolism; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV-1; Immunoglobulin Fab Fragments - isolation & purification; Immunoglobulin Fab Fragments - metabolism; Monoclonal antibodies; monoclonal antibody; Original; Rabbits; Receptors, CCR5 - immunology; Receptors, CCR5 - metabolism; Receptors, CXCR4 - immunology; Receptors, CXCR4 - metabolism; Sheep
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1038/emi.2015.44

The fourth conserved region (C4) in the HIV-1 envelope glycoprotein (Env) gp120 is a structural element that is important for its function, as it binds to both the receptor CD4 and the co-receptor CCR5/CXCR4. It has long been known that this region is highly immunogenic and that it harbors B-cell as well as T-cell epitopes. It is the target of a number of antibodies in animal studies, which are called CD4-blockers. However, the mechanism by which the virus shields itself from such antibody responses is not known. Here, we determined the crystal structure of R53 in complex with its epitope peptide using a novel anti-C4 rabbit monoclonal antibody R53. Our data show that although the epitope of R53 covers a highly conserved sequence 433 AMYAPPI 439 , it is not available in the gp120 trimer and in the CD4-bound conformation. Our results suggest a masking mechanism to explain how HIV-1 protects this critical region from the human immune system.