Structure-Based Design of Hepatitis C Virus E2 Glycoprotein Improves Serum Binding and Cross-Neutralization
Brian G. Pierce, Zhen–Yong Keck, Ruixue Wang, Patrick Lau, Kyle Garagusi, Khadija Elkholy, Eric A. Toth, Richard A. Urbanowicz, Johnathan D. Guest, Pragati Agnihotri, Melissa C. Kerzic, Alexander Marin, Alexander K. Andrianov, Jonathan K. Ball, Roy A. Mariuzza, Thomas R. Fuerst, Steven K. H. Foung
Abstract
Hepatitis C virus infects approximately 1% of the world’s population, and no vaccine is currently available. Due to the high variability of HCV and its ability to actively escape the immune response, a goal of HCV vaccine design is to induce neutralizing antibodies that target conserved epitopes. Here, we performed structure-based design of several epitopes of the HCV E2 envelope glycoprotein to engineer its antigenic properties. Designs were tested in vitro and in vivo , demonstrating alteration of the E2 antigenic profile in several cases, and one design led to improvement of cross-neutralization of heterologous viruses. This represents a proof of concept that rational engineering of HCV envelope glycoproteins can be used to modulate E2 antigenicity and optimize a vaccine for this challenging viral target.