HCV glycoprotein structures: what to expect from the unexpected

•HCV remains a worldwide health problem.•Despite new improved therapies, a cost effective vaccine is indispensable.•HCV glycoproteins are major determinants of viral pathogenicity and immune response.•New structural insight into E1 and E2 provide a major breakthrough in the field.•This information provides the basis for a potential HCV vaccine and drug design.

Hepatitis C virus (HCV) is continuing to spread worldwide, adding three million new infections each year. Currently approved therapies are highly effective; however, access to them is limited due to the high cost of treatment. Therefore, a cost effective vaccine and alternative antivirals remain essential. HCV envelope glycoproteins, E1 and E2, heterodimerize on the virion surface and are the major determinant for virus pathogenicity and host immune response. Recent structural insights into amino-terminal domain of E1 and core of E2 have revealed unexpected folds not present in glycoproteins from related viruses. Here we discuss these structural findings with respect to their role in HCV entry and impact on potential vaccine design and new antivirals.