Since the identification of the hepatitis C virus, great strides have been made in the development of an antiviral therapy. As a crucial mediator of the innate antiviral immune response, interferon-alpha (IFN-alpha) was a natural choice for treatment. Whereas treatment with IFN-alpha alone achieved only modest success, the addition of the broad-spectrum antiviral agent ribavirin greatly improved responses. However, half of the infected individuals with chronic disease do not achieve sustained clearance of hepatitis C virus. To optimize current therapeutic strategies and to develop new therapies, a better understanding of the mechanism of action of IFN and ribavirin will be essential.

Mechanism of action of interferon and ribavirin in treatment of hepatitis C

Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance.

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Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence

https://www.gastrojournal.org/article/S0016-5085(06)02566-2/pdf

Hepatitis C Virus Continuously Escapes From Neutralizing Antibody and T-Cell Responses During Chronic Infection In Vivo

The hepatitis C virus (HCV) is a remarkably successful pathogen, establishing persistent infection in more than two-thirds of those who contract it. Its success is related to its abilities to blunt innate antiviral pathways and to evade adaptive immune responses. These two themes may be related. We propose that HCV takes advantage of the impaired innate response to delay the organization of an effective adaptive immune attack. The tolerogenic liver environment may provide cover, prolonging this delay. HCV's error-prone replication strategy permits rapid evolution under immune pressure. Persistent high levels of viral antigens may contribute to immune exhaustion. Finally, the virus may benefit from the efficient enlistment of memory T and B cells in the pursuit of a moving target.

Flying Under the Radar: The Immunobiology of Hepatitis C

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.21541

Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20253

Effects of antiviral therapy on the cellular immune response in acute hepatitis C

Hepatitis C virus (HCV) infection constitutes a serious global health problem, with more than 120 million people chronically infected. Since the introduction of blood donor screening in the early 1990s, the epidemiology of HCV infection has changed. In the United States, transmission via blood transfusion is now effectively prevented via donor screening [1], and most cases of infection occur in injection drug users via HCV-contaminated needles [2, 3]. In addition, healthcare workers are at risk of infection due to sharp injuries.

Some of the largest studies on virus exposure in healthcare workers were conducted by the Centers for Disease Control and Prevention Needlestick Surveillance Group as multicenter case-control studies. In those studies, healthcare workers who developed antibodies to either HCV [4] or human immunodeficiency virus (HIV) [5] were classified as cases, whereas those who did not seroconvert were classified as controls. Likewise, a large surveillance study in Europe followed 245 healthcare workers for 5 years using seroconversion as evidence of exposure [6].

However, none of these prospective studies assessed HCV-specific T-cell responses. T-cell responses are relevant because the small percentage of patients who clear acute HCV infection spontaneously, approximately 20%, mount vigorous HCV-specific T-cell responses, and T-cell–mediated immune memory may protect humans [7] and chimpanzees [8, 9] upon reexposure. In contrast, antibodies are not required for HCV clearance as shown in hypogammaglobulinemic patients [10], and antibody titers decrease significantly within 10–20 years after HCV clearance [11].

HCV-specific T-cell responses were also described in cross-sectional studies on seronegative subjects such as injection drug users [4, 12–15], family members of HCV-infected patients [16–18], and healthcare workers [19] who test negative for HCV RNA despite an increased risk of HCV exposure. Based on these studies, it has often been suggested that years of low-dose HCV exposure may prime and maintain HCV-specific T cells that protect against systemic infection [13, 14, 17]. However, due to unknown exposure dates and lack of longitudinal immune response analysis, in particular with early time points after exposure, it cannot be excluded that the studied subjects had resolved a regular acute HCV infection in the distant past and subsequently lost HCV-specific antibodies [11].

In the current study, 72 healthcare workers were enrolled upon documented HCV exposure and studied frequently, that is, up to 5 times in the first 6 weeks and at 3 months and 6 months after exposure. In contrast to a previous study that was smaller and had less frequent and later sampling [20], we found a pattern of early transient T-cell responses that was associated with the transmission risk score. Our results support the hypothesis that HCV-specific T cells are more sensitive indicators of low-dose HCV exposure than antibodies, which is relevant for surveillance studies and for vaccine development.

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Yuji Sobao

Papers

Effects of antiviral therapy on the cellular immune response in acute hepatitis C

Occupational Exposure to Hepatitis C Virus: Early T-Cell Responses in the Absence of Seroconversion in a Longitudinal Cohort Study

57 HCV exposure in humans: stimulation of cellular, but not humoral immune responses in the absence of detectable viremia