Functional implications of the binding mode of a human conformation-dependent V2 monoclonal antibody against HIV.
Data from the RV144 HIV vaccine trial indicated that gp120 V2 antibodies were associated with a lower risk of infection; thus, the mapping of V2 epitopes can contribute to the design of an effective HIV vaccine. We solved the crystal structure of human monoclonal antibody (MAb) 2158, which targets a conformational V2 epitope overlapping the α4β7 integrin binding site, and constructed a full-length model of V1V2. Comparison of computational energy stability to experimental enzyme-linked immunosorbent assay (ELISA) results identified a hydrophobic core that stabilizes the V2 region for optimal 2158 binding, as well as residues that directly mediate side chain interactions with MAb 2158. These data define the binding surface recognized by MAb 2158 and offer a structural explanation for why a mismatched mutation at position 181 (I181X) in the V2 loop was associated with a higher vaccine efficiency in the RV144 clinical vaccine trial.


OBJECTIVE
Correlate analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the second variable region (V2) of HIV-1 gp120 was responsible for the modest protection observed in the trial. V2 is a highly variable and immunogenic region, and structural information on its antigenic landscape will be important for rational design of an effective HIV-1 vaccine. Using X-ray crystallography, computational design tools, and mutagenesis assays, we carried out a detailed and systematic investigation of the epitope recognition of human V2 MAb 2158 and demonstrated that its epitope region overlaps the integrin binding site within V2. In addition, we propose a structure-based mechanism for mismatching of the isoleucine at position 181 and the increased vaccine efficacy seen in the RV144 vaccine trial.
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, New York, USA.
Brett
B
Spurrier
Jared
J
Sampson
Miroslaw K
MK
Gorny
Susan
S
Zolla-Pazner
Xiang-Peng
XP
Kong
D016915:AIDS Vaccines / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D015483:HIV Antibodies / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D016915:AIDS Vaccines; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments