JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epiphany Biosciences Inc., San Francisco
The hepatitis C virus (HCV) is a positive-stranded RNA virus classified within the Flaviviridae family. It infects 3-4 MM individuals in the USA alone and an estimated 170 MM worldwide. Around 75% of acute infections develop into life-long infections which are associated with varying levels and types of liver and other diseases. While the majority of infected individuals only have mild forms of hepatitis, some can develop chronic lobular hepatitis that then proceeds sequentially through chronic active hepatitis, liver fibrosis, liver cirrhosis and primary hepatocellular carcinoma. The latter is always preceded by cirrhosis suggesting that the continually-inflamed liver may itself be a direct cause of tumorigenesis. However, certain HCV gene products may also play a role since the nucleocapsid and nonstructural proteins 3 & 4 have been shown to induce tumorigenesis when overexpressed in various cellular and animal models. HCV-associated extrahepatic diseases include mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda and there is some association with non-Hodgkin's B cell lymphoma. The latter may be mediated by the engagement of the HCV receptor, CD81 by envelope glycoprotein 2 within circulating HCV virions.
Many co-factors of HCV-associated disease are known including gender (with the incidence of hepatocellular carcinoma being lower in females), alcohol use, duration of infection and co-infection with other hepatotropic viruses as well as co-infection with HIV. Individuals co-infected with HIV & HCV often develop severe liver disease.
Vaccine strategies to prevent the development of persistent infection are now looking promising. Vaccines eliciting cross-neutralising antibodies or cross-reacting cellular immune responses in non-human primates are able to prevent chronic infection following experimental challenge with heterologous viral strains thus mirroring the correlates of protection in humans that are able to spontaneously eradicate acute HCV infection.
Standard-of-care therapy comprises pegylated alpha-interferon along with ribavirin, a mixture that is thought to have direct antiviral and immunomodulatory activity. Patients with chronic hepatitis and even liver cirrhosis can be normalized by this therapy with virus eradication, although 12 months of treatment are required for the common genotype 1 infections and even then, less than 50% of patients are permanently cured. However, progress is occurring through the use of more specific antivirals that inhibit the viral serine protease, the viral replicase and other targets like nonstructural protein 5a that plays an essential role in virion production. Therefore, we can anticipate a combination therapy to emerge within the next decade that will cure the large majority of HCV patients and a vaccine that could prevent the chronic sequelae of the estimated 25,000 new infections still occurring annually in the USA alone.