Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function

•Membrane-associated positive-strand RNA virus replication.•HCV NS proteins involved in replicase assembly and function.•Structures, mechanisms and functional implications of HCV NS proteins.•HCV antivirals targeting the replicase NS proteins.

Approximately 3% of the world population is infected with hepatitis C virus (HCV), causing a serious public health burden. Like other positive-strand RNA viruses, HCV assembles replicase complexes in association with cellular membranes and produces progeny RNA genomes through negative-strand intermediates. The viral proteins required for RNA replication are nonstructural (NS) proteins NS3 to NS5B. Owing to many obstacles and limitations in structural characterization of proteins and complexes with multiple transmembrane segments, attempts to understand the assembly and action of the HCV replicase complex have been challenging. Nevertheless, great progress has been made in obtaining structural information for several replicase components, providing insights into some aspects of the viral genome replication machinery.