Journal Article

Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design

Seaman, Michael S., Nussenzweig, Michel C., Diskin, Ron, Gnanapragasam, Priyanthi N. P., West, Anthony P., Bjorkman, Pamela J., Gao, Han, Marcovecchio, Paola M., Scheid, Johannes F., Klein, Florian, Abadir, Alexander

2011

Overview

Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46 G54W , a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: AIDS Vaccines / Amino Acid Sequence / Amino acids / Antibodies / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - metabolism / Antibody Affinity / antigens / Atoms / Binding Sites / Biological and medical sciences / Biotechnology / CD4 Antigens - chemistry / CD4 Antigens - metabolism / Complementarity Determining Regions / Crystal structure / Crystallography, X-Ray / Design / Fundamental and applied biological sciences. Psychology / Geometric lines / Grants / HIV / HIV Antibodies - chemistry / HIV Antibodies - immunology / HIV Antibodies - metabolism / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - immunology / HIV Envelope Protein gp120 - metabolism / HIV-1 - immunology / Human immunodeficiency virus / Human immunodeficiency virus 1 / Humans / Hydrogen bonds / Hydrophobic and Hydrophilic Interactions / Immunoglobulin Fab Fragments - chemistry / Immunoglobulin Fab Fragments - immunology / Immunoglobulin Fab Fragments - metabolism / Immunoglobulin Heavy Chains - chemistry / Immunoglobulin Heavy Chains - immunology / Immunoglobulin Heavy Chains - metabolism / Immunoglobulins / Inhibitory concentration 50 / Methods. Procedures. Technologies / Molecular and cellular biology / Molecular Mimicry / Molecular Sequence Data / Mutant Proteins - chemistry / Mutant Proteins - immunology / Mutant Proteins - metabolism / Neutralization / Protein Conformation / Protein Engineering / Protein Structure, Tertiary / Residues / Superposition principle / T lymphocytes / Vaccines / Viruses