Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (30), p.E2083-E2090
• Main Authors: West, Anthony P, Diskin, Ron, Nussenzweig, Michel C, Bjorkman, Pamela J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; antibodies; Base Sequence; Binding sites; Biological Sciences; CD4 Antigens - genetics; CD4 Antigens - metabolism; Conserved Sequence - genetics; crystal structure; Genes; Germ Cells - immunology; Glycoproteins; HIV; HIV Antibodies - genetics; HIV Antibodies - immunology; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV-1; Human immunodeficiency virus; Human immunodeficiency virus 1; humans; Molecular Sequence Data; Mutagenesis; Mutation Rate; Neutralization Tests; PNAS Plus; Sequence Alignment; Sequence Analysis, DNA; Surface Plasmon Resonance; vaccine development
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1208984109

A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies.