Darbha R, Phogat S, Labrijn A, Shu Y, Gu Y, Andrykovitch M, Zhang MY, Pantophlet R, Burton D, Dimitrov D, Ji X; International Conference on AIDS.

Int Conf AIDS. 2002 Jul 7-12; 14: abstract no. LbPeA9003.

NCI-Frederick, NIH, Frederick, United States

BACKGROUND: HIV entry into host cells is initiated by formation of a complex between the viral envelope glycoprotein gp120, the primary receptor CD4 and a coreceptor (typically CCR5 or CXCR4). Recently, a novel broadly neutralizing human monoclonal antibody Fab to HIV-1, X5, was isolated from a phage display library using gp120-CD4-CCR5 trimolecular complexes as screening agents (M. Moulard, S. Phogat, Y. Shu, A. Labrijn, X. Xiao, J. Binley, M.-Y. Zhang, I. Sidorov, C. Broder, J. Robinson, P. Parren, D. Burton, and D. Dimitrov 2002, PNAS, 99, 6913-6918). Of the currently known human monoclonal antibodies with broad neutralizing activity, Fab X5 is the only one that exhibits increased binding to gp120 in the presence of CD4 and CCR5. Methods and RESULTS: The crystal structure of Fab X5 was solved at 1.9 Angstrom resolution. The antibody combining site features a long (22 amino acids) CDR H3 with a protruding hook-shaped motif that may play a critical role in gp120 binding. Docking models of Fab X5 and the known gp120 core structures of HxBc2 and YU2 provide an indication of how X5 may interact with the gp120-CD4 complex. These models are currently being investigated by X5 binding studies to a large panel of gp120 mutants. CONCLUSIONS: The findings further our understanding of conserved, receptor-induced epitopes on gp120 and may provide a template for the design of small-molecule inhibitors of viral entry.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Antibodies, Monoclonal
• Antigens, CD4
• Binding Sites, Antibody
• Crystallization
• Epitopes
• HIV Envelope Protein gp120
• HIV-1
• Humans
• Immunoglobulin Fab Fragments
• Receptors, CCR5
• Receptors, CXCR4
• immunology

Other ID:

• GWAIDS0020884

UI: 102259962

From Meeting Abstracts