Pathophysiology 


HCV is a single-stranded, 9,600-base pair RNA virus of the family Flaviviridae. Its genome encodes a single polyprotein of 3,011 amino acids that are processed into 10 structural and regulatory proteins.2 HCV consists of a core protein and 2 envelope proteins (E1 and E2). In 2 regions on E2, there is a very high rate of mutation attributable to selective pressure by virus-specific antibodies. The nonstructural components consist of NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7. Their proteins function as helicase-, protease-, and RNA-dependent RNA polymerase. NS5A has an interferon sensitivity-determining region (Figure 1). These enzymes are all critical to the replication process of HCV and are promising targets for future antiviral therapy.2

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Unlike HIV or HBV, HCV replicates its genome directly into RNA without a DNA intermediate, so it lacks a latent, nuclear form that defies ready immunological clearance. In order for the virus to exist, it must continuously replicate and may produce more than 10 trillion new viral particles daily.2,4

HCV is not cytopathic, and liver damage is mainly the result of immune-mediated responses. The mechanisms responsible for chronicity and liver lesions in HCV infection are not well understood. CD4+ T cells and their cytokines with inflammatory and regulatory activities may have an important function in the immunopathogenesis of chronic HCV infection. Responses of CD4+ T cells are polarized into type 1 and type 2 helper T-cell (Th1 and Th2) responses. Th1 cells secrete interleukin 2 (IL-2) and interferon gamma, which are important for the initiation of host antiviral immune responses comprising cytotoxic T-lymphocyte (CTL) generation and natural killer (NK)-cell activation. IL-4 and IL-10, produced by Th2 cells, boost the production of antibodies and downregulate the Th1 response. 


Disease progression and the inability to clear HCV infection may result from an imbalance between Th1 and Th2 responses. Patients who clear HCV virus develop a strong Th1 response with a weak or absent Th2 response. Patients who develop chronic HCV infection have a weak Th1 response but a strong Th2 response. Likely, the effect of Th1 cytokines is essential for protection against HCV infection, whereas Th2 cytokines may play a role in inhibiting the host immune system and contribute to the chronicity of the infection.8

The marked nucleotide variability and genetic heterogeneity of HCV (variability between different isolates of 1% to 50%, at least 6 different genotypes, and more than 90 subtypes8) also contribute to its ability to escape the host immune response. Within a genotype, different isolates can vary by 5% to 15%, and virions isolated from a single individual may differ by 1% to 5% owing to RNA-dependent RNA polymerase.6 This replication enzyme lacks proofreading capabilities and creates large quantities of mutant virus, a phenomenon termed quasi-species diversity, which may support virus chronicity.2,5,6 Prior infection with HCV does not protect against later infection with HCV of the same or a different genotype. 


Chronicity


The pathophysiological profile of HCV infection translates into infrequent recovery from acute infection, lack of immunization, and the rapid development of drug resistance.5,8 The rate of spontaneous clearance varies according to the virus, age of the individual at onset of infection, and other factors; approximately 15% to 25% of patients clear the virus without therapy during the first 6 months of infection. In the remaining 75% to 85%, chronic hepatitis develops (Table 2).7


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Although gradual histological progression occurs, the condition is often asymptomatic over a 20- to 30-year period until the complications of advanced liver disease or cirrhosis develop.7 Persistent viremia causes variable degrees of hepatic inflammation and fibrosis, including histological changes of micro- or macrovesicular steatosis, bile duct injury, and lymphocytic follicles.9 Bridging fibrosis and regenerative nodules significantly distort the normal hepatic architecture and result in cirrhosis. In chronic HCV infection, a minimum of 50% of hepatocytes may be infected.2