Estimating the probability of polyreactive antibodies 4E10 and 2F5 disabling a gp41 trimer after T cell-HIV adhesion

• Published in: PLoS computational biology Vol. 10; no. 1; p. e1003431
• Main Authors: Hu, Bin, Liao, Hua-Xin, Alam, S Munir, Goldstein, Byron
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2014; Public Library of Science (PLoS)
• Subjects: Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Neutralizing - chemistry; Biology; Broadly Neutralizing Antibodies; Cell Adhesion; Cell research; Confidence intervals; Epitopes - chemistry; Experiments; Gene expression; Health aspects; HIV (Viruses); HIV Antibodies - chemistry; HIV Envelope Protein gp41 - chemistry; HIV Infections - immunology; HIV Infections - virology; Host-parasite relationships; Humans; Immunoglobulin Fragments - chemistry; Immunoglobulin G - chemistry; Inhibitory Concentration 50; Lymphocytes; Mathematical models; Medicine; Methods; Parameter estimation; Probability; Protein Conformation; Software; T cells; T-Lymphocytes - virology; Viral antibodies; Virus Internalization; United States; Antibodies, Neutralizing; HIV Infections; T-Lymphocytes; HIV Antibodies; Humans; Immunoglobulin G; HIV Envelope Protein gp41; Probability; Antibodies, Monoclonal; Epitopes; Cell Adhesion; Virus Internalization; Immunoglobulin Fragments; Inhibitory Concentration 50; Protein Conformation
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1003431

A few broadly neutralizing antibodies, isolated from HIV-1 infected individuals, recognize epitopes in the membrane proximal external region (MPER) of gp41 that are transiently exposed during viral entry. The best characterized, 4E10 and 2F5, are polyreactive, binding to the viral membrane and their epitopes in the MPER. We present a model to calculate, for any antibody concentration, the probability that during the pre-hairpin intermediate, the transient period when the epitopes are first exposed, a bound antibody will disable a trivalent gp41 before fusion is complete. When 4E10 or 2F5 bind to the MPER, a conformational change is induced that results in a stably bound complex. The model predicts that for these antibodies to be effective at neutralization, the time to disable an epitope must be shorter than the time the antibody remains bound in this conformation, about five minutes or less for 4E10 and 2F5. We investigate the role of avidity in neutralization and show that 2F5 IgG, but not 4E10, is much more effective at neutralization than its Fab fragment. We attribute this to 2F5 interacting more stably than 4E10 with the viral membrane. We use the model to elucidate the parameters that determine the ability of these antibodies to disable epitopes and propose an extension of the model to analyze neutralization data. The extended model predicts the dependencies of IC50 for neutralization on the rate constants that characterize antibody binding, the rate of fusion of gp41, and the number of gp41 bridging the virus and target cell at the start of the pre-hairpin intermediate. Analysis of neutralization experiments indicate that only a small number of gp41 bridges must be disabled to prevent fusion. However, the model cannot determine the exact number from neutralization experiments alone.