Hepatitis C virus- An Overview


Hepatitis C virus (HCV) is a member of the Flaviviridae family, which includes other viruses such as yellow fever virus, dengue fever virus, and West Nile virus. HCV is classified in the Hepacivirus genus, which also includes tamarin virus and GB virus B. HCV is the causative agent of hepatitis C, a chronic liver disease that affects more than 170 million people worldwide.

HCV is an enveloped virus, meaning that it has a lipid membrane derived from the host cell that surrounds its nucleocapsid, which is the protein shell that protects its RNA genome. The lipid membrane contains two envelope glycoproteins, E1 and E2, that are responsible for binding to host cell receptors, mediating membrane fusion, and facilitating viral entry . The envelope glycoproteins form heterodimers (E1/E2) that can further assemble into trimers and pentamers on the surface of the virion.

The HCV genome is a positive-sense single-stranded RNA molecule that is about 9.6 kilobases long . It has a single open reading frame (ORF) that encodes a large polyprotein of about 3000 amino acids, which is then cleaved by host and viral proteases into at least 10 different proteins . The ORF is flanked by untranslated regions (UTRs) at both ends, which are involved in translation initiation and replication of the viral RNA .

The HCV proteins can be divided into structural and nonstructural proteins. The structural proteins are located at the N-terminal part of the polyprotein and include the core protein (C), which forms the nucleocapsid, and the envelope glycoproteins (E1 and E2) . The nonstructural proteins are located at the C-terminal part of the polyprotein and include NS2, NS3, NS4A, NS4B, NS5A, and NS5B . NS2 is a zinc-dependent metalloprotease that cleaves between NS2 and NS3. NS3 is a multifunctional protein that has serine protease and helicase activities. NS4A is a cofactor for NS3 protease. NS4B is a membrane-associated protein that induces the formation of membranous webs where HCV replication occurs. NS5A is a phosphoprotein that regulates viral replication and assembly. NS5B is the RNA-dependent RNA polymerase (RdRp) that synthesizes new viral RNA strands .

The HCV genome has a high degree of genetic diversity due to its error-prone RdRp and high replication rate. There are at least 6 major genotypes and more than 80 subtypes of HCV recognized based on phylogenetic analysis of nucleotide sequences. The genotypes differ by about 30% in their nucleotide sequences, while the subtypes differ by about 15%. The genotypes have different geographic distributions, clinical outcomes, and responses to antiviral therapy.