Rationally designed carbohydrate-occluded epitopes elicit HIV-1 Env-specific antibodies

Cheng Zhu, Elena Dukhovlinova, Olivia Council, Lihua Ping, Edgar M. Faison, Shamit S. Prabhu, E. Lake Potter, Stephen L. Upton, Guowei Yin, James M. Fay, Laura P. Kincer, Ean Spielvogel, Sharon L. Campbell, S. Rahima Benhabbour, Hengming Ke, Ronald Swanstrom () and Nikolay V. Dokholyan ()
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Cheng Zhu: University of North Carolina at Chapel Hill
Elena Dukhovlinova: University of North Carolina at Chapel Hill
Olivia Council: University of North Carolina at Chapel Hill
Lihua Ping: University of North Carolina at Chapel Hill
Edgar M. Faison: University of North Carolina at Chapel Hill
Shamit S. Prabhu: University of North Carolina at Chapel Hill
E. Lake Potter: University of North Carolina at Chapel Hill
Stephen L. Upton: University of North Carolina at Chapel Hill
Guowei Yin: University of North Carolina at Chapel Hill
James M. Fay: University of North Carolina at Chapel Hill
Laura P. Kincer: University of North Carolina at Chapel Hill
Ean Spielvogel: University of North Carolina at Chapel Hill
Sharon L. Campbell: University of North Carolina at Chapel Hill
S. Rahima Benhabbour: University of North Carolina at Chapel Hill
Hengming Ke: University of North Carolina at Chapel Hill
Ronald Swanstrom: University of North Carolina at Chapel Hill
Nikolay V. Dokholyan: University of North Carolina at Chapel Hill

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract An array of carbohydrates masks the HIV-1 surface protein Env, contributing to the evasion of humoral immunity. In most HIV-1 isolates ‘glycan holes’ occur due to natural sequence variation, potentially revealing the underlying protein surface to the immune system. Here we computationally design epitopes that mimic such surface features (carbohydrate-occluded neutralization epitopes or CONE) of Env through ‘epitope transplantation’, in which the target region is presented on a carrier protein scaffold with preserved structural properties. Scaffolds displaying the four CONEs are examined for structure and immunogenicity. Crystal structures of two designed proteins reflect the computational models and accurately mimic the native conformations of CONEs. The sera from rabbits immunized with several CONE immunogens display Env binding activity. Our method determines essential structural elements for targets of protective antibodies. The ability to design immunogens with high mimicry to viral proteins also makes possible the exploration of new templates for vaccine development.

Date: 2019
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DOI: 10.1038/s41467-019-08876-w

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