title: Computational prediction of neutralization epitopes targeted by human anti-V3 HIV monoclonal antibodies.
abstract: The extreme diversity of HIV-1 strains presents a formidable challenge for HIV-1 vaccine design. Although antibodies (Abs) can neutralize HIV-1 and potentially protect against infection, antibodies that target the immunogenic viral surface protein gp120 have widely variable and poorly predictable cross-strain reactivity. Here, we developed a novel computational approach, the Method of Dynamic Epitopes, for identification of neutralization epitopes targeted by anti-HIV-1 monoclonal antibodies (mAbs). Our data demonstrate that this approach, based purely on calculated energetics and 3D structural information, accurately predicts the presence of neutralization epitopes targeted by V3-specific mAbs 2219 and 447-52D in any HIV-1 strain. The method was used to calculate the range of conservation of these specific epitopes across all circulating HIV-1 viruses. Accurately identifying an Ab-targeted neutralization epitope in a virus by computational means enables easy prediction of the breadth of reactivity of specific mAbs across the diversity of thousands of different circulating HIV-1 variants and facilitates rational design and selection of immunogens mimicking specific mAb-targeted epitopes in a multivalent HIV-1 vaccine. The defined epitopes can also be used for the purpose of epitope-specific analyses of breakthrough sequences recorded in vaccine clinical trials. Thus, our study is a prototype for a valuable tool for rational HIV-1 vaccine design.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Shmelkov
authors.affiliation: Public Health Research Institute Center, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Chavdar
authors.initials: C
authors.lastname: Krachmarov
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Arsen V
authors.initials: AV
authors.lastname: Grigoryan
authors.affiliation: Public Health Research Institute Center, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Abraham
authors.initials: A
authors.lastname: Pinter
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Statnikov
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D019295:Computational Biology; D017124:Conserved Sequence; D000939:Epitopes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011487:Protein Conformation; D013045:Species Specificity; D013816:Thermodynamics
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments