Abstract
The only evidence of vaccine-induced protection from HIV acquisition in humans was obtained in the RV144 HIV vaccine clinical trial. One immune correlate of risk in RV144 was observed to be higher titers of vaccine-induced antibodies (Abs) reacting with a 23-mer non-glycosylated peptide with the same amino acid sequence as a segment in the second variable (V2) loop of the MN strain of HIV. We used NMR to analyze the dynamic 3D structure of this peptide. Distance restraints between spatially proximate inter-residue protons were calculated from NOE cross peak intensities and used to constrain a thorough search of all possible conformations of the peptide. α–helical folding was strongly preferred by part of the peptide. A high-throughput structure prediction of this segment in all circulating HIV strains demonstrated that α–helical conformations are preferred by this segment almost universally across all subtypes. Notably, α–helical conformations of this segment of the V2 loop cluster cross-subtype-conserved amino acids on one face of the helix and the variable amino acid positions on the other in a semblance of an amphipathic α–helix. Accordingly, some Abs that protected against HIV in RV144 may have targeted a specific, conserved α–helical peptide epitope in the V2 loop of HIV’s surface envelope glycoprotein.
Highlights
The 25-year evolution of HIV vaccine strategies has been guided in large part by vaccine failures that disabused incorrect notions
It is well established that Cα and Cβ resonance positions, which we obtained for the MN peptide, are sensitive reporters of secondary structure
As our results showed that ab initio folding in the absence of NMR data can accurately assess the 3D structure of this V2 segment in a manner that is consistent with experimental NMR observation, we sought to determine if MN’s α-helical conformation is an anomaly or the rule across circulating strains. ab initio folding can rapidly determine the dynamic structure of the equivalent V2 segment to that of the MN peptide in all circulating strains
Summary
The 25-year evolution of HIV vaccine strategies has been guided in large part by vaccine failures that disabused incorrect notions. The clinical success of previous subunit vaccines. January 20, 2017 α-Helical HIV Protection-Associated Epitope funds from NIH grant P41GM066354, the Keck Foundation, New York State Assembly, and U.S Department of Defense. Antibody binding assays were supported by funding to P.B. provided by the Henry Jackson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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