Differential Reactivity of Germ Line Allelic Variants of a Broadly Neutralizing HIV-1 Antibody to a gp41 Fusion Intermediate Conformation
- 15 November 2011
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (22), 11725-11731
- https://doi.org/10.1128/jvi.05680-11
Abstract
Genetic factors, as well as antigenic stimuli, can influence antibody repertoire formation. Moreover, the affinity of antigen for unmutated naïve B cell receptors determines the threshold for activation of germinal center antibody responses. The gp41 2F5 broadly neutralizing antibody (bNAb) uses the VH2-5 gene, which has 10 distinct alleles that use either a heavy-chain complementarity-determining region 2 (HCDR2) aspartic acid (DH54) or an HCDR2 asparagine (NH54) residue. The 2F5 HCDR2 DH54residue has been shown to form a salt bridge with gp41665K; the VH2-5 germ line allele variant containing NH54cannot do so and thus should bind less avidly to gp41. Thus, the induction of 2F5 bNAb is dependent on both genetic and structural factors that could affect antigen affinity of unmutated naïve B cell receptors. Here, we studied allelic variants of the VH2-5 inferred germ line forms of the HIV-1 gp41 bNAb 2F5 for their antigen binding affinities to gp41 linear peptide and conformational protein antigens. Both VH2-5 2F5 inferred germ line variants bound to gp41 peptides and protein, including the fusion intermediate protein mimic, although more weakly than the mature 2F5 antibody. As predicted, the affinity of the NH54variant for fusion-intermediate conformation was an order of magnitude lower than that of the DH54VH2-5 germ line antibody, demonstrating that allelic variants of 2F5 germ line antibodies differentially bind to gp41. Thus, these data demonstrate a genetically determined trait that may affect host responses to HIV-1 envelope epitopes recognized by broadly neutralizing antibodies and has implications for unmutated ancestor-based immunogen design.This publication has 52 references indexed in Scilit:
- Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodiesNature Structural & Molecular Biology, 2010
- Relationship between Antibody 2F5 Neutralization of HIV-1 and Hydrophobicity of Its Heavy Chain Third Complementarity-Determining RegionJournal of Virology, 2010
- Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitutionProceedings of the National Academy of Sciences of the United States of America, 2010
- Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic toleranceProceedings of the National Academy of Sciences, 2009
- Role of HIV membrane in neutralization by two broadly neutralizing antibodiesProceedings of the National Academy of Sciences, 2009
- Stable Docking of Neutralizing Human Immunodeficiency Virus Type 1 gp41 Membrane-Proximal External Region Monoclonal Antibodies 2F5 and 4E10 Is Dependent on the Membrane Immersion Depth of Their Epitope RegionsJournal of Virology, 2009
- Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogensBiochemical and Biophysical Research Communications, 2009
- Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interfaceProceedings of the National Academy of Sciences of the United States of America, 2009
- A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodiesProceedings of the National Academy of Sciences, 2008
- Human Immunodeficiency Virus Type 1 gp41 Antibodies That Mask Membrane Proximal Region Epitopes: Antibody Binding Kinetics, Induction, and Potential for Regulation in Acute InfectionJournal of Virology, 2008