Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy

Abstract

Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Since its discovery, which dates back to about 30 years ago, many details of the viral genome organization and the astonishing genetic diversity have been unveiled but, owing to the difficulty of culturing HCV in vitro and obtaining fully susceptible yet immunocompetent in vivo models, we are still a long way from the full comprehension of viral life cycle, host cell pathways facilitating or counteracting infection, pathogenetic mechanisms in vivo, and host defences. Here, we illustrate the viral life cycle into cells, describe the interplay between immune and genetic host factors shaping the course of infection, and provide details of the molecular approaches currently used to genotype, monitor replication in vivo, and study the emergence of drug-resistant viral variants.

Keywords: Broadly reactive neutralizing antibodies; Cell culture-derived HCV; Direct antiviral agents; Drug resistance; Genotype; Hepatitis C virus; Host response; Pathogenesis; Quantitative molecular assays; monitoring drug resistance.

Figure 1. The HCV replication cycle

The seven steps of the viral life cycle, indicated in the white boxes, are the following: Attachment, the viral particle, surrounded with lipoproteins, binds the target cells by interacting with several receptors some, most of which shown in figure, considered essential other accessory; Entry: following attachment, the virus enters through clathrin-mediated endocytosis; Uncoating: the cellular and viral membranes fuse and the capsid is disorganized with a process triggered by the low pH of the endosome. After uncoating the positive-strand RNA genome is released into the cytoplasm; Translation: the genomic RNA is directly translated in a polyprotein precursor that is then cleaved into single proteins by both host and viral proteases; Replication: the non-structural proteins and some host factors form a replication complex that synthesized multiple copies of the HCV RNA genome via a minus-strand replicative intermediate; Assembly and maturation: packaging of viral progeny takes place in the endoplasmic reticulum from which the virion acquires the envelope with E1 and E2 glycoproteins. Maturation and association with endogenous lipoproteins to form lipoviral particles immediately follow; Release: virions are released from the cells most likely by exocytosis or transmitted to other cells via a cell-free mechanism.

Figure 2. A schematic of the mutations conferring resistance to NS3, NS5A and NS5B inhibitors

Numbers refer to the amino acid positions correlated to resistance in various HCV genotypes.