title: Constrained peptide models from phage display libraries highlighting the cognate epitope-specific potential of the anti-HIV-1 mAb 2F5.
abstract: The monoclonal antibody 2F5 (mAb 2F5), one of the most potent broadly neutralizing mAbs targeted to the HIV-1 gp41 membrane proximal exterior region (MPER), displays an unusually wide antigenic specificity, tolerating amino acid substitutions at virtually all positions of the 662-ELDKWAS-668 epitope sequence when presented by peptides. Investigating this phenomenon, Menendez et al. [22] concluded that the paratope of 2F5 contains two distinct binding compartments. One is specific and binds the DKW epitope core; the other is multi-specific and binds to the flanking DKW regions that can be distinct from the epitope sequence. Because the DKW-flanking amino acids are strongly conserved in viruses, it is not clear whether the DKW only satisfies the 2F5 epitope recognition demand. In this study, we demonstrate that the specificity of recognition of the epitope depends on the structural context in which the cognate epitope sequence is presented. The antibody does not tolerate any replacements of the DKW-flanking epitope amino acids and binds exclusively to the (L)DKWA sequence provided that it is presented by a 7-mer constrained peptide exposed by the M13 phage pIII protein. Our data propose a novel epitope recognition model in which the 2F5 mAb requires a sequence longer than DKW and no substitution of flanking amino acids for specific recognition of the peptide. Additionally, immunization data supports the notion that the binding and neutralizing immunogenic structural features of the described epitope model do not coincide.
authors.affiliation: Department of Molecular Biology and Biotechnology, Institute of Biomedical Research, Mexican National Autonomous University, Circuito Exterior, Mexico City 04510, Mexico.
authors.forename: Yadira
authors.initials: Y
authors.lastname: Palacios-Rodríguez
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gazarian
authors.forename: Leonor
authors.initials: L
authors.lastname: Huerta
authors.forename: Karlen
authors.initials: K
authors.lastname: Gazarian
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D008969:Molecular Sequence Data; D019151:Peptide Library; D011817:Rabbits
chemical_list: C558560:2F5 monoclonal antibody; D000911:Antibodies, Monoclonal; D000080908:Broadly Neutralizing Antibodies; D000939:Epitopes; D015483:HIV Antibodies; D019151:Peptide Library