What is the role of hepatitis C viral (HCV) proteins in the pathogenesis of infection?

Updated: Oct 07, 2019
  • Author: Vinod K Dhawan, MD, FACP, FRCPC, FIDSA; Chief Editor: BS Anand, MD  more...
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The proteolytic cleavage of the virus results in two structural envelope glycoproteins (E1 and E2) and a core protein. [14] Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, believed to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV. HCV core protein is an important risk factor in the development of liver disease; it can modulate several signaling pathways affecting cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress, and lipid metabolism. [15]

Other viral components are nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7), whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. These nonstructural proteins are necessary for viral propagation and have been the targets for newer antiviral therapies, such as the direct-acting antiviral agents (DAAs). NS2/3 and NS3/4A are proteases responsible for cleaving the HCV polyprotein. NS5A is critical for the assembly of the cytoplasmic membrane-bound replication complex; one region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region. NS5B is an RNA dependent RNA polymerase required for viral replication; it lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1%-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.

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