Kinetics of the Immune Response During Hbv and Hcv Infection

Abstract

The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus

“…Studies of acute HBV infection in primates and humans reveal an initial quiescent phase of Ϸ4-7 weeks before HBV starts to replicate vigorously, reaching levels of 10 9 to 10 10 copies per milliliter (26)(27)(28). Activation of components of the innate immune system are likely to play a central role in control of this initial HBV burst because HBV-DNA quantity decreases by almost 90% well in advance of the appearance of an antigen-specific CD8 ϩ T cell response and hepatopathology (27)(28)(29)(30)(31). However, identification of the individual components of the innate immune system responsible for this rapid down-regulation of viral replication, and the mechanism of activation, has been elusive.…”

Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients

“…Today, there is an increasing evidence that the immune response against hepatitis C virus (HCV), in particular, the cell-mediated response and the host genetic factors contribute to the natural history of HCV infection [1][2][3][4][5][6]. Clinical research showed the prominent role of T helper cell type 1 (Th1) or pro-inflammatory and type 2 (Th2) or anti-inflammatory cytokines in the pathogenesis of chronic hepatitis C. Indeed, a positive correlation between Th1 cytokine levels or Th1-type cell percentage and histological fibrosis or progressive liver injury in chronic hepatitis C was detected [7].…”

Increased frequency of CD56Bright NK‐cells, CD3−CD16+CD56− NK‐cells and activated CD4+T‐cells or B‐cells in parallel with CD4+CDC25High T‐cells control potentially viremia in blood donors with HCV

“…Many hypotheses have been proposed, including the inability of the host to carry out an efficient humoral and cellular response, allowing immune escape of these highly changeable viruses (quasispecies) [Guglietta et al, 2005]; the high rate of HCV replication, which would lead to the exhaustion of CD4 þ T-cells through the production of large amounts of HCV antigens [Kantzanou et al, 2003]; the suppression of HCV-specific CD4 þ T-cell expansion [Klugewitz et al, 2002]; the intrahepatic compartmentalization and induction of apoptosis of virus-specific CD8 þ T-cells [Crispe et al, 2000]; the production of immunomodulatory proteins by HCV [Large et al, 1999]; and the inability of the innate immune response to promote appropriate T-cell stimulation [Bertoletti and Ferrari, 2003].…”