Altered innate immunity in chronic hepatitis C infection: Cause or effect?

Abstract

H epatitis C virus (HCV) is a uniquely successful hepatitis virus in its ability to establish chronic infection in more than two-thirds of those who contract it. The inability of the innate and adaptive immune responses to control HCV invasion and replication contribute to development and persistence of chronic infection. Multiple components have been identified in this process, including pathways by which HCV subverts innate immune recognition and activation, delayed organization of an effective adaptive immune response, the tolerogenic liver environment, and the persistently high levels of viral antigens. We summarize recent findings on the interaction between HCV infection and innate immune responses. Hepatitis C Virus, Immune Responses and Hepatocytes-Brief OverviewA critical role for innate and adaptive immunity has been identified in HCV persistence and liver injury. During acute infection, type I interferon (IFN) is induced in the liver; however, HCV viral load does not decrease, suggesting that HCV interferes with antiviral mechanisms. Innate immune cells, including natural killer cells and dendritic cells shape innate immunity and determine adaptive immune activation. Vigorous, multi-epitopespecific, T helper 1-type and sustained CD4ϩ and CD8ϩ T cell responses were found in resolved acute HCV infections. [1][2][3][4] In contrast, in cases that progress to chronic infection, CD4ϩ T cell responses are weak, short-lived, and targeted to a narrow range of epitopes. 1

The role of chemokines in acute and chronic hepatitis C infection

“…87,88 In addition to this, HCV Core and NS3A proteins have been shown to trigger inflammation through the TLR2/NF-kB pathway. 35,89 This mechanism may represent an evasion strategy whereby HCV inhibits IFN production and exacerbates chronic hepatic inflammation. In contrast, type I IFNs and the NS3/4A protease complex have been shown to downregulate IL-8 expression.…”

Differential alteration of CD56bright and CD56dim natural killer cells in frequency, phenotype, and cytokine response in chronic hepatitis C virus infection

“…More than 90% of patients with acute HCV infection respond to IFN-a-based therapy, while the response rate falls to around 50% for patients with chronic HCV infection (CHC) [7][8][9][10], suggesting a mechanism by which persistent HCV infection leads to resistance to IFN-a-based therapy. The NK cell number has been demonstrated to decrease in patients with CHC [11][12][13][14][15][16], while it is controversial whether NK cell functions are impaired in patients with CHC [17][18][19]. It thus remains unclear whether the perturbation of NK cells, such as that of CD56 bright NK cells or CD56 dim NK cells, is involved in the persistence of CHC as well as the resistance to therapy.…”

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

“…During inflammation, pro-inflammatory cytokines are key factors mediating immune responses [78]. Chronic inflammation plays a multi-faceted role in carcinogenesis [79].…”