HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope

Daniela Fera (), Matthew S. Lee, Kevin Wiehe, R. Ryan Meyerhoff, Alessandro Piai, Mattia Bonsignori, Baptiste Aussedat, William E. Walkowicz, Therese Ton, Jeffrey O. Zhou, Samuel Danishefsky, Barton F. Haynes and Stephen C. Harrison
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Daniela Fera: Harvard Medical School
Matthew S. Lee: Harvard Medical School
Kevin Wiehe: Duke University Medical Center
R. Ryan Meyerhoff: Duke Human Vaccine Institute
Alessandro Piai: Harvard Medical School
Mattia Bonsignori: Duke University Medical Center
Baptiste Aussedat: Sloan Kettering Institute
William E. Walkowicz: Sloan Kettering Institute
Therese Ton: Swarthmore College
Jeffrey O. Zhou: Swarthmore College
Samuel Danishefsky: Sloan Kettering Institute
Barton F. Haynes: Duke University Medical Center
Stephen C. Harrison: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.

Date: 2018
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DOI: 10.1038/s41467-018-03565-6

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