An RNA virus, designated hepatitis G virus (HGV), was identified from the plasma of a patient with chronic hepatitis. Extension from an immunoreactive complementary DNA clone yielded the entire genome (9392 nucleotides) encoding a polyprotein of 2873 amino acids. The virus is closely related to GB virus C (GBV-C) and distantly related to hepatitis C virus, GBV-A, and GBV-B. HGV was associated with acute and chronic hepatitis. Persistent viremia was detected for up to 9 years in patients with hepatitis. The virus is transfusion-transmissible. It has a global distribution and is present within the volunteer blood donor population in the United States.

The mechanisms by which hepatitis C virus (HCV) induces chronic infection in the vast majority of infected individuals are unknown. Sequences within the HCV E1 and E2 envelope genes were analyzed during the acute phase of hepatitis C in 12 patients with different clinical outcomes. Acute resolving hepatitis was associated with relative evolutionary stasis of the heterogeneous viral population (quasispecies), whereas progressing hepatitis correlated with genetic evolution of HCV. Consistent with the hypothesis of selective pressure by the host immune system, the sequence changes occurred almost exclusively within the hypervariable region 1 of the E2 gene and were temporally correlated with antibody seroconversion. These data indicate that the evolutionary dynamics of the HCV quasispecies during the acute phase of hepatitis C predict whether the infection will resolve or become chronic.

To clarify the relationship between hepatitis C virus infection and the development of hepatocellular carcinoma as sequelae of non-A, non-B posttransfusion hepatitis, 231 patients with chronic non-A, non-B hepatitis (96 with chronic hepatitis, 81 with cirrhosis and 54 with hepatocellular carcinoma) were analyzed for antibody to hepatitis C virus and were compared with 125 patients with chronic hepatitis B (50 with chronic hepatitis, 46 with cirrhosis and 29 with hepatocellular carcinoma). Antibody to hepatitis C virus was detected in 89.6%, 86.4% and 94.4% of patients with non-A, non-B hepatitis-related chronic hepatitis, cirrhosis and hepatocellular carcinoma, respectively, compared with 6%, 17.4% and 34.5% with similar diseases related to hepatitis B. A history of transfusion was documented in 52%, 33% and 42% of anti-hepatitis C virus-positive cases of chronic hepatitis, cirrhosis and hepatocellular carcinoma. The mean intervals between the date of transfusion and the date of diagnosis of anti-hepatitis C virus-positive chronic hepatitis, cirrhosis and hepatocellular carcinoma were 10, 21.2 and 29 yr, respectively. In 21 patients with transfusion-associated hepatocellular carcinoma, anti-hepatitis C virus was present in each serial sample available for testing, including samples obtained up to 14 yr before the diagnosis of hepatocellular carcinoma. These data suggest the slow, sequential progression from acute hepatitis C virus-related non-A, non-B hepatitis through chronic hepatitis and cirrhosis to hepatocellular carcinoma and support a causal association between hepatitis C virus and hepatocellular carcinoma.

Hepatitis C has emerged in recent years as the most common basis for liver disease in the United We conclude with the view that severe, life-threatening, progressive liver disease clearly occurs in a sizable minority (perhaps 30%) of chronically infected persons but speculate that fibrosis progression is neither linear or inevitable and hence that most hepatitis C virus carriers will have either a stable nonprogressive course or such indolent pro- ObjectivesUpon completion of this article, the reader should recognize: 1) the influence of study design on estimates of HCV disease severity; 2) that the rate of spontaneous recovery from HCV infection is higher than previously considered; 3) that fibrosis progression is not linear and is influenced by cofactors, particularly alcohol; 4) that it is likely that the majority of HCV infected individuals will not develop cirrhosis or other life threatening complications of their infection; and 5) that although the individual risk of developing severe complications may be less than 30%, the societal burden of HCV infection is very high because of the high prevalence and global distribution of the agent. AccreditationThe Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. The Indiana University School of Medicine takes responsibility for the contents, quality, and scientific integrity of this activity. CreditThe Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours credit toward the AMA Physicians Recognition Award in category one. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. DisclosureStatements have been obtained regarding the authors' relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the author of this article.Downloaded by: Karolinska Institutet. Copyrighted material.

The cellular immune response contributes to clearance of hepatitis C virus (HCV) and persists for decades after recovery from infection. The immunological basis for the inefficiency of the cellular immune response in chronically infected persons is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, to investigate at the single-cell level effector function and phenotype of HCV-specific CD8+ T cells in 20 chronically infected and 12 long-term recovered patients. Overall, HCV-specific, tetramer+ T cells were more frequently found in PBMCs of chronically infected patients than in those of recovered patients. However, when compared with HCV-tetramer+ T cells of recovered patients, they displayed an impaired proliferative capacity. As a result of the impaired proliferative capacity, HCV-specific T cell lines derived from chronically infected patients displayed less peptide-specific cytotoxicity than those from recovered patients. In addition, proliferation and ex vivo IFN-γ production of HCV-tetramer+ cells, but not influenza-virus-specific T cells, were defective in chronically infected patients and could not be restored by in vitro stimulation with peptide and IL-2. At least three distinct phenotypes of HCV-specific CD8+ T cells were identified and associated with certain functional characteristics. In addition, impairment of proliferative, cytokine, and cytotoxic effector functions of tetramer+ T cells in viremic patients was associated with weak ex vivo HCV-specific CD4+ T cell responses. Thus, the defective functions of HCV-specific CD8+ T cells might contribute to viral persistence in chronically infected patients, and knowledge on their reversibility may facilitate the development of immunotherapeutic vaccines.