Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide and thus represents a viral pandemic, one that is five times as widespread as infection with the human immunodeficiency virus type 1 (HIV-1). The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure. Progression to chronic disease occurs in the majority of HCV-infected persons, and infection with the virus has become the main indication . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200107053450107?listPDF=true

Hepatitis C Virus Infection

Approximately 4 million persons in the United States and probably more than 100 million persons worldwide are infected with hepatitis C virus. The virus has the unique ability to cause persistent infection in susceptible hosts after parenteral or percutaneous transmission, and its underlying mechanisms are not well understood. The immunologic correlates of protection and viral clearance and the pathogenesis of liver injury are yet to be defined, but recent studies suggest the importance of cell-mediated immune responses. Although 70% to 80% of infected persons become chronic carriers, most have relatively mild disease with slow progression. However, chronic and progressive hepatitis C carries significant morbidity and mortality and is a major cause of cirrhosis, end-stage liver disease, and liver cancer. Development of an effective hepatitis C virus vaccine is not imminent, but recent advances in technology and basic knowledge of molecular virology and immunology have engendered novel approaches to the fundamental problems encountered in vaccine development. Current therapy for hepatitis C, although effective in some patients, is problematic and still evolving. Advances in modern biology and immunology promise new therapies for this important disease.

Pathogenesis, natural history, treatment, and prevention of hepatitis C.

https://www.gastrojournal.org/article/S0016-5085(99)70353-7/pdf

Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.510300312

Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence.

Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor-α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.

Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man

In acute hepatitis C virus infection, 50 to 70% of patients develop chronic disease. Considering the low rate of spontaneous viral clearance during chronic hepatitis C infection, the first few months of interaction between the patient’s immune system and the viral population seem to be crucial in determining the outcome of infection. We previously reported the association between a strong and sustained CD4 1 T-cell response to nonstructural protein 3 (NS3) of the hepatitis C virus and a self-limited course of acute hepatitis C infection. In this study, we identify an immunodominant CD4 1 T-cell epitope (amino acids 1248 to 1261) that was recognized by the majority (14 of 23) of NS3-specific CD4 1 T-cell clones from four of five patients with acute hepatitis C infection. This epitope can be presented to CD4 1 T cells by HLA-DR4, -DR11, -DR12, -DR13, and -DR16. HLA-binding studies revealed a high binding affinity for 10 of 13 common HLA-DR alleles. Two additional CD4 1 T-cell epitopes, amino acids 1388 to 1407 and amino acids 1450 to 1469, showed a very narrow pattern of binding to individual HLA-DR alleles. Our data suggest that the NS3-specific CD4 1 T-cell response in acute hepatitis C infection is dominated by a single, promiscuous peptide epitope which could become a promising candidate for the development of a CD4 1 T-cell vaccine. Hepatitis C virus (HCV) infection has an estimated worldwide prevalence of 0.3 to 1.5% and is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1, 15). More than 50% of acute infections lead to chronic disease (2), and once chronic infection is established, spontaneous recovery is exceptional. Therefore, characterization of the antiviral immune response during the first few weeks of acute hepatitis C infection in patients with self-limited disease as opposed to those developing chronic hepatitis C may allow the identification of successful antiviral immune strategies. In two recent studies of patients with acute hepatitis C infection, a strong association between a vigorous and sustained HCVspecific CD4 1 T-cell response and a self-limited course of acute hepatitis C infection could be demonstrated (5, 16). Although the CD4 1 T-cell response was directed against several HCV antigens (core, E2, nonstructural protein 3 [NS3], NS4, and NS5), in the majority of patients with self-limited disease, the response to NS3 was frequently strongest and was detected most consistently. In this study, we identify one immunodominant CD4 1 T-cell epitope within the NS3 protein that is recognized by the majority of patients with self-limited acute hepatitis C infection and which binds promiscuously to the most common HLA-DR alleles.

/pdf/immunodominant-cd4-t-cell-epitope-within-nonstructural-57x8mgejw3.pdf

Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection.

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Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection.