HCV core protein and virus assembly: what we know without structures

Abstract

Chronic hepatitis C virus (HCV) infection results in a progressive disease that may end in cirrhosis and, eventually, in hepatocellular carcinoma. In the last several years, tremendous progress has been made in understanding the HCV life cycle and in the development of small molecule compounds for the treatment of chronic hepatitis C. Nevertheless, the complete understanding of HCV assembly and particle release as well as the detailed characterization and structure of HCV particles is still missing. One of the most important events in the HCV assembly is the nucleocapsid formation which is driven by the core protein, that can oligomerize upon interaction with viral RNA, and is orchestrated by viral and host proteins. Despite a growing number of new factors involved in HCV assembly process, we do not know the three-dimensional structure of the core protein or its topology in the nucleocapsid. Since the core protein contains a hydrophobic C-terminal domain responsible for the binding to cellular membranes, the assembly pathway of HCV virions might proceed via coassembly at endoplasmic reticulum membranes. Recently, new mechanisms involving viral proteins and host factors in HCV particle formation and egress have been described. The present review aims to summarize the advances in our understanding of HCV assembly with an emphasis on the core protein as a structural component of virus particles that possesses the ability to interact with a variety of cellular components and is potentially an attractive target for the development of a novel class of anti-HCV agents.

Fig. 1

The functional map of HCV core protein. The core protein is released from polyprotein by a signal peptidase (SP). Next the precursor core of 191 amino acids is processed by a signal peptide peptidase (SPP), giving a mature protein of around 177 amino acids that is composed of two domains, D1 and D2. Based on the charge distribution, the D1 domain can be subdivided into three basic clusters: BD1 (basic domain 1), BD2 (basic domain 2) and BD3 (basic domain 3). The D2 domain contains two amphipathic α-helices, Helix I (HI) and Helix II (HII), separated by a hydrophobic loop (HL)

Fig. 2

Model of HCV particle production. (a) HCV particle formation starts on or near the surface of LDs, most probably concurrently with envelopment at the ER, and continues through the secretory pathway in association with components of VLDL synthesis in order to produce a mature form of lipoviroparticles coupled with the specific lipoproteins (depicted by yellow color). (b) Core interacts with NS5A on the surface or in the close proximity of LDs so the viral RNA can be packed into the newly formed core oligomers. This event most probably triggers the capsid assembly. p7 recruits the core assembly intermediate to the ER membrane and is necessary for the final steps of capsid assembly and the initiation of budding. NS2 brings replication and assembly sites in the close vicinity through its interaction between glycoproteins, E1 and E2, and NS3/4A