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Publication Abstract from PubMed

The RV144 HIV vaccine trial indicated that gp120 V2 antibodies were associated with 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 that targets a conformational V2 epitope overlapping the alpha4beta7 integrin binding site, and constructed a full-length model of V1V2. Comparison of computational energy stability to experimental ELISA results identified a hydrophobic core, stabilizing the V2 region for optimal 2158 binding, and 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 mismatching mutation at position 181 (I181X) in the V2 loop is associated with a vaccine efficiency of 78% in the RV144 clinical vaccine trial.IMPORTANCE Correlates 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 for its antigenic landscape will be important for a rational design of an effective HIV-1 vaccine. Using X-ray crystallography, computational design tools, and mutagenesis assays, we have 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 proposed a structural based mechanism for mismatching of isoleucine at position 181 with increased vaccine efficacy seen in the RV144 vaccine trial.

Functional Implications of the Binding Mode of a Human Conformation-dependent V2 Monoclonal Antibody against HIV.,Spurrier B, Sampson J, Gorny MK, Zolla-Pazner S, Kong XP J Virol. 2014 Jan 29. PMID:24478429^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.