Antigenic structures of HCV envelope glycoproteins (Env)

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PROJECT SUMMARY/ABSTRACT Hepatitis C virus (HCV) chronically infects ~1% of the global population, predisposing patients to chronic liver disease and liver cancer. To control and eventually eradicate this major public health threat, a molecular understanding of the HCV surface antigens is one of highest priorities in HCV research to aid in rational design of effective vaccines. The HCV surface envelope proteins (Env), comprised of heterodimers of the E1 and E2 glycoproteins, are responsible for viral attachment and entry into host cells and for assembly of infectious virus particles. The E1 and E2 glycoproteins are also the main targets of neutralizing antibodies in the immune system. The overall goals of Project 1 of this P01 proposal are to determine high-resolution structures of HCV envelope glycoproteins and engineered vaccine antigens by X-ray crystallography and electron microscopy. The Specific Aims of this project are (1) To determine the antigenic landscape of E1E2 immune epitopes; (2) To determine the structure of E2 in complex with host receptor CD81; and (3) To determine the structure of E1E2 complex. These structures will be critical for understanding the HCV entry mechanism and the immune response at the atomic level which in turn will enable structure-based approaches for rational design and engineering of E1E2-based vaccine candidates in Project 2 of this P01 proposal.