The long way toward understanding host and viral determinants of therapeutic success in HCV infection

Abstract

The T helper type 1 (Th1)/Th2 hypothesis of immune regulation arose in the late 1980s, stemming from observations in mice [1]. Since then, the Th1/Th2 cytokine balance has been extensively described in humans as a pivotal component of antiviral immunity and pathogenesis in infections. In a simplistic view of the literature, Th1 cells are commonly associated with interferon-gamma (IFN-c), interleukin (IL)-2 and IL-12 secretion, and these cells are hypothesized to mediate the response against intracellular pathogens such as viruses. Inversely, Th2 cells, which are most heavily reliant on IL-4, IL-5, IL-10 and IL-13, are supposed to emphasize protection against extracellular pathogens. In its modern incarnation, the role played by the Th1/Th2 balance in the regulation of cellular immunity against infections seems vaster and influenced by a large number of natural variables [2, 3]. In addition, since 1986 and the emergence of the Th1/Th2 hypothesis, other T-cell subpopulations, such as Th17 cells, have been described as functionally integrated actors of the antiinfectious immunity and crucial component of an effective response against pathogens [4]. Despite increasing evidence demonstrating the importance of these subpopulations in the effectiveness of the immune response against pathogens, the Th1/Th2 balance remains a critical ratio to clear invaders. For hepatitis C virus (HCV), a robust Th1 cell response and a mild Th2 activity, with a vigorous multi-epitopespecific CD4 and CD8 T-cell responses, are associated with HCV clearance in chronic infection [5]. IFN-c, a cytokine strongly associated with the Th1 response, exerts direct and durable antiviral effects inhibiting the replication of subgenomic and genomic HCV RNAs by stimulating the cytotoxic T-lymphocyte response. In patients with chronic hepatitis C, the cytotoxic CD8 T-cell activity may also be inversely related to the viral load. Viral sequence mutations are an important mechanism to escape the adaptative cellular immune response. A high level of replication, high mutation rate (estimated to be 1 in 1000 bases per year) due to the lack of proof-reading capacity of its polymerase, and pre-existing quasi-species contribute to the rapid diversification of the viral population and limits the efficiency of an adaptive immune response [6]. In addition, infiltrated cells in the liver belong mostly to the Th1 cells, unable to secrete IL-4 and IL-5 [7]. In this context, the overproduction of the initially protective immune response and soluble factors at the site of infection leads to adverse effects resulting in hepatocellular damage. Th1 cells release TNF-a, IFN-c, and IL-2 causing selfinflicted inflammation and necrosis. To limit these events and the persistence of HCV, the Th1 immune response must be kept under control. Th2 cells such as IL-4and IL-10-secreting cells have a vital role in protecting the host from the potentially damaging consequences of Th1 cells in chronic HCV infection by suppressing the Th1 response and counteracting the fibrogenic effects of TNF-a, IFN-c, and IL-2. On the other hand, the Th2 response is also more frequently associated with viral persistence and resistance to treatment in contrast to the viral clearance associated with Th1 [8]. Hence, intrahepatic IL-10-producing T cells are more frequently detected in patients with chronic hepatitis. An increased Th1 and Th2 response has been shown during chronic HCV infection with a greater elevated level of Th2 than Th1 cytokines [9]. This suggests that an enhanced Th2 response is at least partly responsible P.-A. Rubbo (&) P. Van de Perre E. Tuaillon INSERM U1058, CHU Montpellier and Montpellier 1 University, Montpellier, France e-mail: pierrealainrubbo@gmail.com