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Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies. Due to the challenges in determining experimental structures, structural information on E1 and E2 and their interaction is relatively limited, providing opportunities to model the structures, interactions, and dynamics of these proteins. This review highlights efforts to model the E2 glycoprotein structure, the assembly of the functional E1E2 heterodimer, the structure and binding of human coreceptors, and recognition by key neutralizing antibodies. We also discuss a comparison of recently described models of full E1E2 heterodimer structures, a simulation of the dynamics of key epitope sites, and modeling glycosylation. These modeling efforts provide useful mechanistic hypotheses for further experimental studies of HCV envelope assembly, recognition, and viral fitness, and underscore the benefit of combining experimental and computational modeling approaches to reveal new insights. Additionally, computational design approaches have produced promising candidates for epitope-based vaccine immunogens that specifically target key epitopes, providing a possible avenue to optimize HCV vaccines versus using native glycoproteins. Advancing knowledge of HCV envelope structure and immune recognition is highly applicable toward the development of an effective vaccine for HCV and can provide lessons and insights relevant to modeling and characterizing other viruses.

Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies. Due to the challenges in determining experimental structures, structural information on E1 and E2 and their interaction is relatively limited, providing opportunities to model the structures, interactions, and dynamics of these proteins. This review highlights efforts to model the E2 glycoprotein structure, the assembly of the functional E1E2 heterodimer, the structure and binding of human coreceptors, and recognition by key neutralizing antibodies. We also discuss a comparison of recently described models of full E1E2 heterodimer structures, a simulation of the dynamics of key epitope sites, and modeling glycosylation. These modeling efforts provide useful mechanistic hypotheses for further experimental studies of HCV envelope assembly, recognition, and viral fitness, and underscore the benefit of combining experimental and computational modeling approaches to reveal new insights. Additionally, computational design approaches have produced promising candidates for epitope-based vaccine immunogens that specifically target key epitopes, providing a possible avenue to optimize HCV vaccines versus using native glycoproteins. Advancing knowledge of HCV envelope structure and immune recognition is highly applicable toward the development of an effective vaccine for HCV and can provide lessons and insights relevant to modeling and characterizing other viruses. [ABSTRACT FROM AUTHOR]