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Tan SL, editor. Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk (UK): Horizon Bioscience; 2006.

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Hepatitis C Viruses: Genomes and Molecular Biology.

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Chapter 14Regulation of Adaptive Immunity by HCV

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Abstract

HCV causes chronic infection in the majority of infected patients, which is associated with attenuated adaptive immunity against the virus. Accumulating data suggest that HCV may modulate the adaptive anti-HCV immunity of the host to facilitate the establishment of viral persistence. Potential mechanisms of this modulation include infection of dendritic cells by HCV, as well as binding of HCV envelope or core proteins to cell surface receptors, resulting in perturbation of the functions of different immune cell subsets. These mechanisms may operate predominantly in the liver, the primary site of infection by HCV, where the unique hepatic environment favors tolerance rather than immunity to foreign antigens. Elucidation of these mechanisms may lead to development of novel therapeutic strategies combining both antiviral drugs and immunotherapy agents.

Introduction

Hepatitis C virus (HCV) is a major blood-borne virus that infects over 100 million people worldwide and 2.7 million in the United States. It is estimated that in less than 20% of HCV-infected individuals the virus is cleared spontaneously, while in the majority of patients the virus persists and causes chronic hepatitis that may lead to end-stage liver diseases requiring liver transplantation (Alter et al., 1999). The mechanisms underlying different outcomes of infection are not clear at this time. The host immune responses, including innate immunity and adaptive immunity, play a critical role in determining the outcome of viral infection, as well as in the nature and extent of liver cell injury during HCV infection (Rehermann and Chisari, 2000; He and Greenberg, 2002). Since the rate of persistence for HCV is much higher than other hepatitis viruses, for example, hepatitis B virus (HBV) that persists in only less than 10% of immunocompetent adults who are infected (Hollinger and Liang, 2001), HCV appears to be more successful than many other viruses in terms of evading the protective immunity of the host. However, little is known regarding the exact reasons for the failure of the host immune system in fighting HCV. In this article the current knowledge regarding the adaptive immunity to HCV will be reviewed first, followed by a discussion on the potential mechanisms HCV may employ to interfere with the normal functions of host immune system to achieve its persistence.

Adaptive Immunity to HCV: A Failure in Most Patients

Although HCV persists in the majority of infected individuals, a small fraction of patients can successfully clear the infecting virus. In a study on injection drug users, those who resolved previous HCV infection were 12 times less likely to be reinfected to develop persistent infection than people infected for the first time. In those who did become reinfected, the median peak HCV RNA levels were two logs lower than people infected for the first time to develop persistent infection. These findings suggest that a protective immunity does exist, which is capable of complete or partial control of HCV infection (Mehta et al., 2002).

While the role of neutralizing antibodies in the protective immunity against HCV has recently regained attention (Hsu et al., 2003; Logvinoff et al., 2004), most of the previous studies on the human adaptive immune responses against HCV focused on the T cell responses. Although the number of cases with self-limited HCV infection that have been carefully studied is relatively small, such studies usually reveal a vigorous HCV-specific T cell response, including CD4 T cell response (Gerlach et al., 1999; Takaki et al., 2000; Thimme et al., 2001; Rosen et al., 2002) and CD8 T cell response (Gruner et al., 2000; Lechner et al., 2000b; Takaki et al., 2000; Thimme et al., 2001; Lauer et al., 2004). These responses were detected early during the acute phase (Takaki et al., 2000; Thimme et al., 2001) and sustained for many years after the clearance of HCV (Takaki et al., 2000). They were usually broadly targeted at multiple epitopes restricted by different MHC molecules, without a dominant epitope (Cooper et al., 1999; Lauer et al., 2004). In contrast, patients with chronic HCV infection usually have weak or defected T cell responses against HCV, as indicated by low frequencies for the specific T cells (He et al., 1999; Lauer et al., 2004), short-lived responses (Lechner et al., 2000a; Ulsenheimer et al., 2003), narrowly targeted epitopes (Lauer et al., 2004), as well as defects in the effector functions of the specific T cells (Gruener et al., 2001; Wedemeyer et al., 2002). Taken together, these studies strongly suggest that the host T cell responses are a key factor in determining the outcome of HCV infection. Of note, during the acute phase of self-limited HCV infection, a brief period of dysfunction of HCV-specific CD8 T cells has also been documented (Lechner et al., 2000b; Thimme et al., 2001), suggesting that a transient down-modulation of the effector functions of specific CD8 T cells may be a host strategy to limit the tissue damage caused by the cytotoxic CD8 T cells at the early stage of infection when viral replication is at its peak rate.

Although it is still unclear why T cell responses fail to clear HCV in most cases, a comparison of T cell immunity against HCV and other viruses with different outcomes of infection has generated some intriguing results. Within the category of persistent viruses, the pattern of viral replication varies from latent infections that undergo periodic reactivation (e.g. Epstein-Barr virus, EBV), to ongoing low-level viral replication (e.g. human cytomegalovirus, CMV) controlled by the immune responses without causing disease, to persistent high-level viral replication subjected to immune control to variable extents at different stages of disease course, as in the case of HIV. MHC class I tetramers and cytokine flow cytometry assays have been used to characterize phenotypes of human CD8 T cell responses to persistent viral pathogens (He et al., 1999; Appay et al., 2000; Gamadia et al., 2001; Hislop et al., 2001; Catalina et al., 2002; Khan et al., 2002; Wedemeyer et al., 2002). A study comparing the phenotypes of peripheral CD8 T cells specific for HIV, CMV, EBV and HCV showed that the expression of CD8 T cell surface markers thought to be related to CD8 T cell differentiation, including CD27 and CD28, were heterogeneous between CD8 T cells specific for different viruses (Appay et al., 2002). The authors proposed the use of CD27 and CD28 expression to classify virus-specific CD8 T cells into early (CD27+CD28+), intermediate (CD27+CD28) and late (CD27CD28) differentiated cells. Interestingly, CD8 T cells specific for each of the four viruses appeared to fall into different stages based upon this classification; that is, HCV-specific CD8 T cells had markers associated with the early differentiation phenotype, EBV-specific CD8 T cells were classified as early-intermediate, CD8 T cells recognizing HIV antigens were intermediate, and only CMV-specific CD8 T cells had the proposed late phenotype. Of note, memory CD8 T cells specific for influenza A virus (fluA), which causes transient infections and is cleared by the immune system, have phenotypes consistent with those of early differentiated cells (He et al., 2003).

Although the mechanisms explaining these heterogeneous phenotypes of virus-specific T cells are not known, there appears to be a correlation between the differentiation stage of virus-specific CD8 T cells and the control of viral replication mediated by the CD8 T cell response. CMV is a persisting virus with ongoing low-level viral replication, but it does not cause any disease in immune competent subjects; this is associated with high levels of fully differentiated effector CD8 T cells that control the ongoing replication of virus. On the other end of the spectrum, fluA does not persist in infected host. The fluA-specific memory T cells responsible for the long-term maintenance of immunity in healthy subjects are experiencing rest from stimulation by viral antigens (Wherry and Ahmed, 2004); this is associated with their early differentiation phenotypes. Between these two extremes lies EBV, which is a latent virus with periodic reactivation that re-stimulates the resting memory T cells briefly at intervals, resulting in an early-intermediate phenotype of the EBV-specific CD8 T cells. HIV causes a persistent and progressive infection. This is associated with an intermediate differentiation phenotype of HIV-specific CD8 T cells with certain functional defects when compared to CMV-specific CD8 T cells (Appay et al., 2000; Champagne et al., 2001). Such an immune response may partially control the ongoing viral replication during the asymptomatic phase, until the depletion of helper CD4 T cells leads to the collapse of the immune system and onset of AIDS.

However, when HCV-specific CD8 T cells are compared to CD8 T cells specific for the other viruses, they do not fit into the general pattern described above. While HCV causes persistent infection and ongoing disease, HCV-specific CD8 T cells, if ever detected in the peripheral blood, are frequently found to have a phenotype consistent with an early differentiation stage, similar to the resting fluA-specific memory CD8 T cells which had not been exposed to the virus since the last acute influenza was cleared. Some of the HCV-specific CD8 T cells even appeared to be functional when stimulated ex vivo with the endogenous viral peptides of the patient (He et al., unpublished data). In other words, HCV-specific CD8 T cells in many patients appear to be in a state of rest or anergy in vivo, ignoring the ongoing HCV infection. Of particular interest is a recent study on a cohort of patients co-infected with HCV and CMV, which found that CMV-specific CD8 T cells in these patients appeared to have lost some markers associated with differentiation maturity, including increased expression of CCR7 and reduced expression of Fas and perforin, although they maintained functional responses to in vitro stimulation with CMV antigen (Lucas et al., 2004). The authors suggested that the reduction in mature CD8 T cells in HCV-infected individuals arises through either impairment or regulation of T cell stimulation, or through the early loss of mature T cells. In either case, HCV may have a pervasive influence on the general T cell immunity of infected hosts, which is not limited to HCV-specific T cells.

A critical factor for the development and differentiation of T cells into functional memory and effector cells is the stimulation that they receive during the primary response (Lanzavecchia and Sallusto, 2002). In order to understand the apparent weak or abnormal T cell immunity to HCV, it is important to investigate the initial events leading to the antiviral adaptive immunity, which is the processing and presentation of viral antigens.

Dendritic Cells–Are They Infected by HCV?

While B and T lymphocytes are the effectors of the adaptive immunity, their development and function is under the control of dendritic cells (DCs). Different subsets of DCs, including myeloid-derived DCs (MDC) and plasmacytoid-derived DCs (PDC), are the most important antigen presenting cells with the capability to capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate B and T cell responses (Banchereau et al., 2000). DCs not only activate lymphocytes, they also have the important function of tolerizing T cells to self-antigens, which results in the anergic state of such cells to avoid autoimmune reactions (Banchereau et al., 2000). The two opposite roles of DCs have been related to different maturity and cytokine production patterns of DCs (Crispe, 2003; Kubo et al., 2004). Thus, depending on the nature of antigens as foreign or self, the functions of DCs have to be precisely controlled to either activate or tolerize T cells. Any perturbation to this control may lead to serious consequences. These include impaired immunity to infecting pathogens, causing persistent infections; or abnormal immunity to self-antigens, causing autoimmune diseases. In addition to functioning as antigen presenting cells that play a key role in the induction of adaptive immunity or immune tolerance, DC is also an important part of the antiviral innate immunity which is largely mediated by the type I interferons (IFNs) produced by PDCs (Cella et al., 1999).

Many viruses can directly infect DCs through different cell surface receptors. In response to this invasion, DCs process viral proteins and present them through MHC class I and II pathways while undergoing a maturation that enhances their presentation of antigen to T cells and expression of T cell costimulation factors for induction of adaptive T cell antiviral immunity (Carbone and Heath, 2003; Rinaldo and Piazza, 2004). As a strategy to counteract antiviral immunity, some viruses have evolved mechanisms to undermine the functions of DCs. For example, infection of DCs by measles virus resulted in diminished IL-12 production and inhibition of DC maturation (Schneider-Schaulies et al., 2003; Servet-Delprat et al., 2003). HIV-infected subjects had defects in the number, immunophenotype and functions of blood DC subsets infected with HIV (Barron et al., 2003; Donaghy et al., 2003). Infection of DCs by CMV has also been shown to cause inhibition of DC maturation and T cell activation, as well as increased production of molecules that induce apoptosis in T cells and down-regulation of MHC class I molecules (Raftery et al., 2001; Moutaftsi et al., 2002).

Accumulating evidence suggests that DCs are susceptible to HCV infection. In some studies, HCV RNA sequences, including replicative negative-strand RNA, have been detected in DCs isolated from patients with chronic HCV infection (Bain et al., 2001; Goutagny et al., 2003; Tsubouchi et al., 2004a). It was reported that both immature and mature monocyte-derived DCs were infected with HCV, as indicated by detection of negative-strand HCV RNA in the cells incubated in vitro with HCV-positive serum samples (Navas et al., 2002). In a study of HCV RNA sequencies isolated from liver and DC samples of a patient, the quasispecies detected in DCs were unique and differed from those present in the liver, suggesting a particular tropism of HCV quasispecies for DCs. Moreover, the translational activity of DC-derived HCV was significantly impaired when compared with those from liver and PBMCs, suggesting an impaired replication of HCV in the DCs (Laporte et al., 2003). Infection of DCs by HCV is thought to be mediated by the interaction of the HCV glycoprotein E2 with DC-SIGN, a membrane-associated C-type lectin that also involves in the binding of HIV to DCs (Lozach et al., 2003; Pohlmann et al., 2003).

Several groups have reported dysfunction of DCs that may potentially affect adaptive immunity in patients with persistent HCV infection, using various in vitro functional assays for DCs. These include impaired allostimulatory abilities to CD4 T cells (Kanto et al., 1999; Auffermann-Gretzinger et al., 2001; Bain et al., 2001; Kanto et al., 2004; Tsubouchi et al., 2004a), defects in responding to maturation stimuli (Auffermann-Gretzinger et al., 2001), as well as impaired ability to secrete IL-12, a cytokine important for the development of CD4 helper T cell responses (Anthony et al., 2004; Kanto et al., 2004). Some of these defects were reversed after IFN-α therapy that cleared HCV in the sera (Auffermann-Gretzinger et al., 2001) or DCs (Tsubouchi et al., 2004b), indicating that the DC dysfunction is associated with HCV infection. Interestingly, a positive association was observed between MDC-associated IL-12 production and HCV-specific T cell frequency in HCV-infected subjects (Anthony et al., 2004). The DC-mediated innate antiviral immunity also appeared to be impaired in HCV-infected patients, as indicated by reduced production of IFN-α by PDCs (Anthony et al., 2004; Kanto et al., 2004). Of note, IFN-α is not only an important antiviral cytokine; it is also an important modulator for adaptive immunity. It has been reported that IFN-α enhances expression of class I and class II molecules, cytokines and perforin that are involved in the presentation of viral antigens and the effector functions of T cells (Ji et al., 2003), as well as provides a stimulating signal for the clonal expansion and differentiation of CD8 T cells (Curtsinger et al., 2005).

In addition to the dysfunction of DCs, the numbers of MDCs, PDCs and DC progenitors in the periphery were significantly lower in patients with chronic hepatitis than in healthy controls (Kanto et al., 2004; Wertheimer et al., 2004). Taken together, these findings point to a defective immune response mediated by HCV-induced DC dysfunction as a potential mechanism enabling the persistent HCV infection.

It should be mentioned that most of the reported DC dysfunctions were based on monocyte-derived DCs generated in vitro. While this system has been used extensively in studying DC biology, it is not clear to what extend this model represents the functions of DCs in vivo (Kanto and Hayashi, 2004), especially those in the infected liver. In addition, conflicting results have been reported by other investigators who had conducted similar studies but failed to detect monocyte-derived DC dysfunction in HCV chronically infected patients (Longman et al., 2004) or chimpanzees (Rollier et al., 2003; Larsson et al., 2004), the only animal model for HCV infection. Obviously, more studies are warranted to elucidate the exact role of DCs in the apparent HCV-specific immunodeficiency.

Interference of Host Cell Functions by HCV

While it is still controversial in terms of DC dysfunction in HCV-infected patients, in vitro studies have shown that various HCV proteins have the potential capability to modulate host cell functions by interfering with cellular signal transduction. Numerous interactions between HCV proteins and cellular components have been identified in cell lines or experimental mice by using different expression systems for HCV proteins (Tellinghuisen and Rice, 2002). Studies have showed that the expression of HCV proteins suppressed IFN-induced signal transduction through the JAK-STAT pathway (Heim et al., 1999; Blindenbacher et al., 2003; Geiss et al., 2003; Duong et al., 2004). Specifically, a recent study in transfected cell line demonstrate that expression of HCV proteins suppressed IFN signaling by degrading STAT1, a major signal protein of the JAK-STAT pathway (Lin et al., 2005). HCV NS3/4A serine protease blocks viral activation of IFN regulatory factor-3 (IRF-3), a key transcription factor in inducing type I IFN expression, by proteolytic cleavage of a cellular protein in the IRF-3 signaling pathway (Foy et al., 2003), while HCV NS5A and E2 inhibits the IFN-inducible protein kinase PKR thought to play a role in the antiviral effect of IFN (Gale et al., 1999; Taylor et al., 1999). In addition to their central role in the innate immunity against viral infections, type I IFNs also exert modulation functions to the adaptive antiviral immunity (Boehm et al., 1997; Foster, 1997; Ji et al., 2003; Diepolder, 2004; Curtsinger et al., 2005). Of particular interest, DCs are a key component of both innate immunity and adaptive immunity, which orchestrate a successful overall immune response against infecting viruses. In an intriguing in vivo mouse study, Sarobe et al. used recombinant adenovirus vectors encoding HCV core/E1 or NS3 proteins to demonstrate that expression of specific HCV proteins in DCs down-modulated the antiviral adaptive immunity (Sarobe et al., 2003). The authors found that the expression of core/E1 proteins in DCs inhibited their maturation. When mice were immunized with immature DCs transduced with an adenovirus encoding core/E1, lower CD4 and CD8 T cell responses were induced in comparison to the mice receiving DCs transduced with an adenovirus encoding NS3.

In addition to the effects of intracellularly expressed HCV proteins, the interference of cellular functions by extracellular HCV proteins binding to cell surface receptors has also been documented. CD81 is a cell surface marker that binds the major envelope protein E2 of HCV (Pileri et al., 1998), and has been suggested to be involved in the infection process of HCV (McKeating et al., 2004; Zhang et al., 2004). It was reported that engagement of CD81 with exogenous HCV E2 affected multiple functions of natural killer (NK) cells including activation, cytokine production, proliferation, and cytotoxic granule release (Crotta et al., 2002; Tseng and Klimpel, 2002). While the NK cell is a primary effector of the innate immune system, a complex interaction exists between NK cells and DCs (Andrews et al., 2005), which may lead to activation or killing of DCs, depending on the nature of the interaction (Ferlazzo et al., 2002; Gerosa et al., 2002; Moretta, 2002; Piccioli et al., 2002; Zitvogel, 2002). This indicates an important role of NK cells in the regulation of adaptive immunity to infections. It has been shown in a mouse model that NK cells are necessary for optimal priming of adenovirus-specific T cells (Liu et al., 2000). Of particular interest, in a study on the regulation of NK cell activities by inhibitory receptor CD94/NKG2A that normally leads to NK cell-induced activation of DCs, NK cells from chronic HCV-infected donors were not capable of activating DCs under the same conditions. In comparison to NK cells from normal donors, those from HCV-infected patients showed higher expression of the inhibitory receptor CD94/NKG2A and the cytokines IL-10 and TGF-β (Jinushi et al., 2004). Therefore, modulation of NK cells could be another potential pathway for HCV to affect the host innate and adaptive immune responses.

While E2 is a major component of HCV envelope and is readily available in HCV-positive serum for interaction with cell surface receptors, it was reported that free HCV core protein was secreted from stable transfectant cell lines (Sabile et al., 1999) and could be detected in the serum of HCV-infected patients as well (Maillard et al., 2001). In a series of publications, Hahn and colleagues reported in vivo and in vitro studies suggesting that HCV core acts as an immunomodulator for the host T cell response. They first demonstrated that the core protein of HCV genotype 1a delivered by a recombinant vaccinia vector suppressed the immune response to the vaccinia virus in mice (Large et al., 1999). Using in vitro cell systems, they further showed that the core protein bound to the complement receptor gC1qR on T cells and inhibited their proliferation and IFN-γ production (Kittlesen et al., 2000; Yao et al., 2001; Yao et al., 2003; Yao et al., 2004). Based on these results, a model has been proposed that HCV core acts as an immune modulator that binds to a component of the host complement system and suppresses T cell responses, leading to the persistence of HCV (Eisen-Vandervelde et al., 2004). This is an attractive model because the binding of C1q, the natural ligand for gC1qR, to T cells is already known to suppress T cell response (Chen et al., 1994). In addition, other pathogens, including measles virus, EBV, and HIV, also appear to exploit similar strategies to suppress the host immune system by interactions with components of the host complement machinery (Fingeroth et al., 1984; Viscidi et al., 1989; Karp et al., 1996).

However, the role of HCV core as an immunomodulator is still an issue of debate, as similar studies using the core of HCV genotype 1b delivered with a recombinant adenovirus vector, or using genotype 1b core transgenic mouse, both failed to demonstrate any immunomodulatory effects on virus-induced cellular immunity (Sun et al., 2001; Liu et al., 2002). If the immunomodulator function of HCV core is a unique feature of HCV genotype 1a but not genotype 1b, this does not explain the fact that both HCV strains are equally likely to establish persistent infection. Therefore, this model needs direct evidence from human clinical studies, as well as more vigorous testing with in vivo experimental systems, including chimpanzees.

Regulatory T Cells in HCV Infection

Regulatory T cells (Tregs) have been recognized to be an important modulator of T cell immunity in recent years. The most studied Tregs are those with the phenotype CD4+CD25+, which have been shown to be powerful inhibitors of T cell activation both in vivo and in vitro (Shevach, 2002). While the involvement of Tregs in human autoimmune diseases such as multiple sclerosis and myasthenia gravis has been established (Viglietta et al., 2004; Balandina et al., 2005), the potential role of Tregs in viral hepatitis is just beginning to be defined. They could limit liver injury by controlling inflammation, or they may promote persistence of infection by suppressing immune responses (Chang, 2005). Recently, increased numbers of these cells have been linked to the impaired immune response in patients with chronic HBV infection (Stoop et al., 2005). In chronic HCV infection, the persistence of HCV was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequencies of CD4+CD25+ Tregs that could directly suppress HCV-specific CD8 T cells ex vivo (Sugimoto et al., 2003; Cabrera et al., 2004). However, these studies did not answer the question of whether the abnormalities of Tregs associated with persistent HCV infection are the causes or the consequences of chronic HCV infection.

Studies in mice have linked the immune regulatory function of Tregs to DCs (Pasare and Medzhitov, 2003). It was reported recently that the suppressive function of Tregs was critically dependent on immature DCs and was readily reversed by the maturation of DCs (Kubo et al., 2004), indicating that the maturity of DCs is a key factor that determines suppression or activation of adaptive immune response. Therefore, if the functions of DCs are indeed modulated by HCV infection, Tregs may provide another potential pathway for HCV to manipulate host adaptive immunity to benefit its persistence.

Immune Cells and Immune Responses in the Liver

Fig. 1 is a summary of the aforementioned potential mechanisms for the regulation of adaptive immunity by HCV. It should be emphasized that these models are largely based on in vitro or ex vivo experiments using human immune cells isolated from peripheral blood or on mouse experiments and have not been verified in HCV infected patients. A major challenge to all these potential mechanisms, or the HCV-induced dysfunctions of different immune cell subsets including DCs, NKs and T cells, is that they are not in agreement with the lack of global immune deficiency in HCV-infected individuals similar to that in HIV-infected individuals. In other words, these mechanisms cannot explain why only HCV-specific immune responses are impaired, while the immune responses against other pathogens appear to be spared from the HCV-mediated immune dysfunctions. Although a recent study suggested that in patients with chronic HCV infection the phenotypes of CMV-specific CD8 T cells were affected, there was no evidence for functional defects of CMV immunity (Lucas et al., 2004).

Fig. 1. Potential mechanisms for HCV-mediated interference of adaptive immunity.

Fig. 1

Potential mechanisms for HCV-mediated interference of adaptive immunity. All these mechanisms are likely to operate primarily in the liver.

The primary site of HCV replication and the major location of disease caused by HCV are both in the liver, where most of the immunopathologic events associated with the infection are likely to occur. This notion is supported by the dramatic lymphocyte infiltration in the inflamed liver, but not in the normal liver. Unfortunately, because of the difficulty in obtaining liver specimens, most of the immunological studies on human liver diseases have to rely on peripheral blood samples. Although very little is known about the immune cells in human liver compared to their counterparts in the peripheral blood, evidences derived from limited studies that directly investigated immune cells in normal and HCV-infected livers have revealed significant differences between the intrahepatic and peripheral lymphocyte subsets, including their activation status, phenotypes and proliferation capability (Nuti et al., 1998; Wang et al., 2004; Ward et al., 2004). By using MHC tetramers, HCV-specific CD8 T cells in the liver have been characterized directly. These studies revealed that such cells were enriched in HCV-infected liver versus peripheral blood and had different surface phenotypes compared to their counterparts in the periphery (He et al., 1999; Grabowska et al., 2001; Accapezzato et al., 2004). Of note, studies in mice have demonstrated a highly heterogeneous nature of hepatic DCs and identified unique intrahepatic DC subsets with phenotypic and functional features distinct from DC subsets isolated from other sites (Lian et al., 2003).

As the largest organ in the body, the liver not only has various excretory, detoxifying and metabolic functions, but it is also considered an intrinsic lymphoid organ (Mackay, 2002) with unique microenvironment compared to other lymphoid tissues in the periphery, such as the lymph nodes. Therefore, naive T cells in the liver may encounter local antigens and start development and differentiation in a manner distinct from those in the periphery, including such dramatic differences as apoptosis versus proliferation (Park et al., 2002). It has been shown in mice that oral administration of a foreign antigen at high dosage generated CD4 Tregs that suppressed T cell proliferation as well as Ab responses to the antigen (Watanabe et al., 2002). Of particular interest, Bowen et al. recently demonstrated in mice that the site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. They showed that while naive CD8 T cells activated within the lymph nodes were capable of mediating hepatitis, cells undergoing primary activation within the liver exhibited defective cytotoxic function and shortened half-life and did not mediate hepatocellular injury (Bowen et al., 2004). These findings emphasized the unique nature of immune responses in the liver versus the periphery.

The intrahepatic tolerance can be considered a requirement for the special functions of the liver. The incoming blood stream from the intestine to the liver carries large amount of food-derived antigens that are foreign in nature but mainly harmless to the body. The constant presence of non-self antigens in the liver is thought to impose a constraint on the immune responses generated in the liver, resulting in a tolerant environment for foreign antigens (Crispe, 2003). The unique tolerance nature of liver is best demonstrated by the fact that allogeneic liver transplantation can be established without immunosuppression (Calne et al., 1969). However, this constraint on liver immunity does not prevent the immune system from mounting vigorous responses against some liver-specific pathogens such as hepatitis A virus, which is almost always cleared after a self-limited infection (Hollinger and Emerson, 2001), and HBV, which is also cleared in more than 90% of immunocompetent adults (Hollinger and Liang, 2001). Obviously, a precise control on the actions of the intrahepatic immune cells is in operation, leading to either tolerance or immunity to foreign antigens.

Although the controlling mechanism for liver tolerance is poorly understood at this time, it is reasonable to speculate that liver resident antigen presenting cells, including DCs, liver sinusoidal endothelial cells (Knolle and Limmer, 2001) and liver resident machrophages or Kupffer cells (Everett et al., 2003), play a critical role in shaping the outcome of intrahepatic immune responses. In addition to the professional antigen presenting cells, hepatocytes may also serve as antigen presenting cells under certain conditions (Herkel et al., 2003). It has been shown in mice that liver sinusoidal endothelial cells selectively suppressed the expansion of IFN-γ-producing Th1 cells but promoted the outgrowth of IL-4-expressing Th2 cells, creating an immune suppressive milieu that favors development of tolerance rather than immunity within the liver (Klugewitz et al., 2002). In particular, the accessory signals delivered by the hepatic antigen presenting cells, including cytokines and costimulating molecules, are likely to exert profound effects on the regulation of intrahepatic T cell immunity (Crispe, 2003). Given that liver is the primary site of replication for HCV with the highest concentration of viral protein products, it is conceivable that HCV-mediated interference of immune cell functions (Fig. 1), including those of HCV-infected DCs or other antigen presenting cells as well as NK cells and T cells, occurs primarily in the liver rather than other sites of the body, resulting in a suppressed immunity against HCV but relatively unaffected immune responses against other pathogens that do not primarily infect the liver. Future studies on the issue of HCV-mediated immune modulation should focus on the relevant events in the liver that affect the function of intrahepatic immune cells.

Conclusion

Although the mechanism for HCV to evade host immune responses and establish chronic infection is still poorly understood, accumulating data indicate that HCV may play an active role in attenuating host adaptive immunity to benefit its persistence. Therefore, suppression of HCV replication by antiviral treatment should restore the T cell immunity against HCV. Indeed, in HCV chronically-infected patients treated with IFN, increased T cell immunity after IFN therapy has been demonstrated for HCV-specific CD4 T cells (Cramp et al., 2000; Barnes et al., 2002; Kamal et al., 2002) and CD8 T cells (Vertuani et al., 2002; Morishima et al., 2003), although in some studies an increase in HCV-specific CD8 T cells was not detected (Barnes et al., 2002). The discrepancy could be caused by different methods and antigens used to measure CD8 response and should be resolved by further studies.

While current pegylated IFN-based anti-HCV therapies have accomplished greatly improved efficacy, the rate of sustained virological response is still less than 50% for the most common genotype of HCV (Manns et al., 2001; Fried et al., 2002). In a significant fraction of patients who failed to achieve long-term response, however, the HCV replication was temporally suppressed during IFN treatment. This may represent an opportunity for immunotherapy such as therapeutic vaccines designed to enhance adaptive immunity against HCV. With the HCV viral load suppressed by IFN, the therapeutic vaccine is likely to elicit an anti-HCV immunity most efficiently. Therefore a combination of antiviral drugs and a therapeutic vaccine may produce a synergetic effect that surpasses the potential of either treatment strategy alone.

References

  1. Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, Abrignani S, Mondelli MU, Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest. 2004;113:963–972. [PMC free article: PMC379326] [PubMed: 15057302]
  2. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS. The Prevalence of Hepatitis C Virus Infection in the United States 1988 through 1994. N Engl J Med. 1999;341:556–562. [PubMed: 10451460]
  3. Andrews DM, Andoniou CE, Scalzo AA, van Dommelen SL, Wallace ME, Smyth MJ, Degli-Esposti MA. Cross-talk between dendritic cells and natural killer cells in viral infection. Mol Immunol. 2005;42:547–555. [PubMed: 15607812]
  4. Anthony DD, Yonkers NL, Post AB, Asaad R, Heinzel FP, Lederman MM, Lehmann PV, Valdez H. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol. 2004;172:4907–4916. [PubMed: 15067070]
  5. Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med. 2002;8:379–385. [PubMed: 11927944]
  6. Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA, et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med. 2000;192:63–75. [PMC free article: PMC1887711] [PubMed: 10880527]
  7. Auffermann-Gretzinger S, Keeffe EB, Levy S. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood. 2001;97:3171–3176. [PubMed: 11342445]
  8. Bain C, Fatmi A, Zoulim F, Zarski JP, Trepo C, Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology. 2001;120:512–524. [PubMed: 11159892]
  9. Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005;105:735–741. [PMC free article: PMC1847365] [PubMed: 15454488]
  10. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811. [PubMed: 10837075]
  11. Barnes E, Harcourt G, Brown D, Lucas M, Phillips R, Dusheiko G, Klenerman P. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology. 2002;36:743–754. [PubMed: 12198669]
  12. Barron MA, Blyveis N, Palmer BE, MaWhinney S, Wilson CC. Influence of plasma viremia on defects in number and immunophenotype of blood dendritic cell subsets in human immunodeficiency virus 1-infected individuals. J Infect Dis. 2003;187:26–37. [PubMed: 12508143]
  13. Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, et al. Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology. 2003;124:1465–1475. [PubMed: 12730885]
  14. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–795. [PubMed: 9143706]
  15. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest. 2004;114:701–712. [PMC free article: PMC514586] [PubMed: 15343389]
  16. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40:1062–1071. [PubMed: 15486925]
  17. Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM, Binns RM, Davies DA. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223:472–476. [PubMed: 4894426]
  18. Carbone FR, Heath WR. The role of dendritic cell subsets in immunity to viruses. Curr Opin Immunol. 2003;15:416–420. [PubMed: 12900273]
  19. Catalina MD, Sullivan JL, Brody RM, Luzuriaga K. Phenotypic and functional heterogeneity of EBV epitope-specific CD8+ T cells. J Immunol. 2002;168:4184–4191. [PubMed: 11937579]
  20. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med. 1999;5:919–923. [PubMed: 10426316]
  21. Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001;410:106–111. [PubMed: 11242051]
  22. Chang KM. Regulatory T cells and the liver: a new piece of the puzzle. Hepatology. 2005;41:700–702. [PubMed: 15789365]
  23. Chen A, Gaddipati S, Hong Y, Volkman DJ, Peerschke EI, Ghebrehiwet B. Human T cells express specific binding sites for C1q. Role in T cell activation and proliferation. J Immunol. 1994;153:1430–1440. [PubMed: 8046223]
  24. Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, Parham P, Walker CM. Analysis of a successful immune response against hepatitis C virus. Immunity. 1999;10:439–449. [PubMed: 10229187]
  25. Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology. 2000;118:346–355. [PubMed: 10648463]
  26. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003;3:51–62. [PubMed: 12511875]
  27. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, Mosca M, Filliponi F, Brunetto RM, Bonino F, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002;195:35–41. [PMC free article: PMC2196014] [PubMed: 11781363]
  28. Curtsinger JM, Valenzuela JO, Agarwal P, Lins D, Mescher MF. Cutting edge: type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol. 2005;174:4465–4469. [PubMed: 15814665]
  29. Diepolder HM. Interferon-alpha for hepatitis C: antiviral or immunotherapy? J Hepatol. 2004;40:1030–1031. [PubMed: 15158347]
  30. Donaghy H, Gazzard B, Gotch F, Patterson S. Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1. Blood. 2003;101:4505–4511. [PubMed: 12576311]
  31. Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology. 2004;126:263–277. [PubMed: 14699505]
  32. Eisen-Vandervelde AL, Waggoner SN, Yao ZQ, Cale EM, Hahn CS, Hahn YS. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem. 2004;279:43479–43486. [PubMed: 15292184]
  33. Everett ML, Collins BH, Parker W. Kupffer cells: another player in liver tolerance induction. Liver Transpl. 2003;9:498–499. [PubMed: 12740793]
  34. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med. 2002;195:343–351. [PMC free article: PMC2193591] [PubMed: 11828009]
  35. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci U S A. 1984;81:4510–4514. [PMC free article: PMC345620] [PubMed: 6087328]
  36. Foster GR. Interferons in host defense. Semin Liver Dis. 1997;17:287–295. [PubMed: 9408964]
  37. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, Gale M Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145–1148. [PubMed: 12702807]
  38. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982. [PubMed: 12324553]
  39. Gale M Jr, Kwieciszewski B, Dossett M, Nakao H, Katze MG. Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase. J Virol. 1999;73:6506–6516. [PMC free article: PMC112733] [PubMed: 10400746]
  40. Gamadia LE, Rentenaar RJ, Baars PA, Remmerswaal EB, Surachno S, Weel JF, Toebes M, Schumacher TN, ten Berge IJ, van Lier RA. Differentiation of cytomegalovirus-specific CD8(+) T cells in healthy and immunosuppressed virus carriers. Blood. 2001;98:754–761. [PubMed: 11468176]
  41. Geiss GK, Carter VS, He Y, Kwieciszewski BK, Holzman T, Korth MJ, Lazaro CA, Fausto N, Bumgarner RE, Katze MG. Gene expression profiling of the cellular transcriptional network regulated by alpha/beta interferon and its partial attenuation by the hepatitis C virus nonstructural 5A protein. J Virol. 2003;77:6367–6375. [PMC free article: PMC155033] [PubMed: 12743294]
  42. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, Hoffmann R, Schirren CA, Santantonio T, Pape GR. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology. 1999;117:933–941. [PubMed: 10500077]
  43. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002;195:327–333. [PMC free article: PMC2193595] [PubMed: 11828007]
  44. Goutagny N, Fatmi A, De Ledinghen V, Penin F, Couzigou P, Inchauspe G, Bain C. Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J Infect Dis. 2003;187:1951–1958. [PubMed: 12792872]
  45. Grabowska AM, Lechner F, Klenerman P, Tighe PJ, Ryder S, Ball JK, Thomson BJ, Irving WL, Robins RA. Direct ex vivo comparison of the breadth and specificity of the T cells in the liver and peripheral blood of patients with chronic HCV infection. Eur J Immunol. 2001;31:2388–2394. [PubMed: 11500822]
  46. Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, Walker B, Sullivan J, Phillips R, Pape GR, Klenerman P. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol. 2001;75:5550–5558. [PMC free article: PMC114267] [PubMed: 11356962]
  47. Gruner NH, Gerlach TJ, Jung MC, Diepolder HM, Schirren CA, Schraut WW, Hoffmann R, Zachoval R, Santantonio T, Cucchiarini M, et al. Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C [In Process Citation] J Infect Dis. 2000;181:1528–1536. [PubMed: 10823750]
  48. He XS, Greenberg HB. CD8+ T-cell response against hepatitis C virus. Viral Immunol. 2002;15:121–131. [PubMed: 11952134]
  49. He XS, Mahmood K, Maecker HT, Holmes TH, Kemble GW, Arvin AM, Greenberg HB. Analysis of the frequencies and of the memory T cell phenotypes of human CD8+ T cells specific for influenza A viruses. J Infect Dis. 2003;187:1075–1084. [PubMed: 12660922]
  50. He XS, Rehermann B, Lopez-Labrador FX, Boisvert J, Cheung R, Mumm J, Wedemeyer H, Berenguer M, Wright TL, Davis MM, Greenberg HB. Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers. Proc Natl Acad Sci U S A. 1999;96:5692–5697. [PMC free article: PMC21922] [PubMed: 10318946]
  51. Heim MH, Moradpour D, Blum HE. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J Virol. 1999;73:8469–8475. [PMC free article: PMC112866] [PubMed: 10482599]
  52. Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S, Kanzler S, Blessing M, Schmitt E, Lohse AW. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology. 2003;37:1079–1085. [PubMed: 12717388]
  53. Hislop AD, Gudgeon NH, Callan MF, Fazou C, Hasegawa H, Salmon M, Rickinson AB. EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function. J Immunol. 2001;167:2019–2029. [PubMed: 11489984]
  54. Hollinger F B, Emerson S U. Hepatitis A virus. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 799–840.
  55. Hollinger FB, Liang TJ. Hepatitis B virus. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 2971–3036.
  56. Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM, McKeating JA. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A. 2003;100:7271–7276. [PMC free article: PMC165865] [PubMed: 12761383]
  57. Ji X, Cheung R, Cooper S, Li Q, Greenberg HB, He XS. Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C. Hepatology. 2003;37:610–621. [PubMed: 12601359]
  58. Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004;173:6072–6081. [PubMed: 15528343]
  59. Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology. 2002;123:1070–1083. [PubMed: 12360469]
  60. Kanto T, Hayashi N. Distinct susceptibility of dendritic cell subsets to hepatitis C virus infection: a plausible mechanism of dendritic cell dysfunction. J Gastroenterol. 2004;39:811–812. [PubMed: 15338382]
  61. Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A, Sasaki Y, Kasahara A, Hori M. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol. 1999;162:5584–5591. [PubMed: 10228041]
  62. Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T, Oki C, Itose I, Hiramatsu N, Takehara T, et al. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis. 2004;190:1919–1926. [PubMed: 15529255]
  63. Karp CL, Wysocka M, Wahl LM, Ahearn JM, Cuomo PJ, Sherry B, Trinchieri G, Griffin DE. Mechanism of suppression of cell-mediated immunity by measles virus. Science. 1996;273:228–231. [PubMed: 8662504]
  64. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth J A, Sinclair A J, Nayak L, Moss P A. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. In: Knipe DM HP, editor. J Immunol. Philadelphia: Lippincott Williams and Wilkins; 2002. pp. 1984–1992. [PubMed: 12165524]
  65. Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest. 2000;106:1239–1249. [PMC free article: PMC381434] [PubMed: 11086025]
  66. Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle PA, Hamann A, Crispe IN. Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization. J Immunol. 2002;169:2407–2413. [PubMed: 12193708]
  67. Knolle PA, Limmer A. Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol. 2001;22:432–437. [PubMed: 11473832]
  68. Kubo T, Hatton RD, Oliver J, Liu X, Elson CO, Weaver CT. Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLR-activated dendritic cells. J Immunol. 2004;173:7249–7258. [PubMed: 15585847]
  69. Lanzavecchia A, Sallusto F. Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol. 2002;2:982–987. [PubMed: 12461571]
  70. Laporte J, Bain C, Maurel P, Inchauspe G, Agut H, Cahour A. Differential distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells. Blood. 2003;101:52–57. [PubMed: 12393733]
  71. Large MK, Kittlesen DJ, Hahn YS. Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence. J Immunol. 1999;162:931–938. [PubMed: 9916717]
  72. Larsson M, Babcock E, Grakoui A, Shoukry N, Lauer G, Rice C, Walker C, Bhardwaj N. Lack of phenotypic and functional impairment in dendritic cells from chimpanzees chronically infected with hepatitis C virus. J Virol. 2004;78:6151–6161. [PMC free article: PMC416524] [PubMed: 15163708]
  73. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Robbins GK, Casson DR, Reiser M, et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology. 2004;127:924–936. [PubMed: 15362047]
  74. Lechner F, Gruener NH, Urbani S, Uggeri J, Santantonio T, Kammer AR, Cerny A, Phillips R, Ferrari C, Pape GR, Klenerman P. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol. 2000a;30:2479–2487. [PubMed: 11009080]
  75. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med. 2000b;191:1499–1512. [PMC free article: PMC2213430] [PubMed: 10790425]
  76. Lian ZX, Okada T, He XS, Kita H, Liu YJ, Ansari AA, Kikuchi K, Ikehara S, Gershwin ME. Heterogeneity of dendritic cells in the mouse liver: identification and characterization of four distinct populations. J Immunol. 2003;170:2323–2330. [PubMed: 12594254]
  77. Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard JT, Schmidt EV, Chung RT. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology. 2005;128:1034–1041. [PubMed: 15825084]
  78. Liu ZX, Govindarajan S, Okamoto S, Dennert G. NK cells cause liver injury and facilitate the induction of T cell-mediated immunity to a viral liver infection. J Immunol. 2000;164:6480–6486. [PubMed: 10843705]
  79. Liu ZX, Nishida H, He JW, Lai MM, Feng N, Dennert G. Hepatitis C virus genotype 1b core protein does not exert immunomodulatory effects on virus-induced cellular immunity. J Virol. 2002;76:990–997. [PMC free article: PMC135789] [PubMed: 11773374]
  80. Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci U S A. 2004;101:10149–10154. [PMC free article: PMC454180] [PubMed: 15220475]
  81. Longman RS, Talal AH, Jacobson IM, Albert ML, Rice CM. Presence of functional dendritic cells in patients chronically infected with hepatitis C virus. Blood. 2004;103:1026–1029. [PubMed: 14525790]
  82. Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A, Houles C, Fieschi F, Schwartz O, Virelizier JL, et al. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J Biol Chem. 2003;278:20358–20366. [PubMed: 12609975]
  83. Lucas M, Vargas-Cuero AL, Lauer GM, Barnes E, Willberg CB, Semmo N, Walker BD, Phillips R, Klenerman P. Pervasive influence of hepatitis C virus on the phenotype of antiviral CD8+ T cells. J Immunol. 2004;172:1744–1753. [PubMed: 14734757]
  84. Mackay IR. Hepatoimmunology: a perspective. Immunol Cell Biol. 2002;80:36–44. [PubMed: 11869361]
  85. Maillard P, Krawczynski K, Nitkiewicz J, Bronnert C, Sidorkiewicz M, Gounon P, Dubuisson J, Faure G, Crainic R, Budkowska A. Nonenveloped nucleocapsids of hepatitis C virus in the serum of infected patients. J Virol. 2001;75:8240–8250. [PMC free article: PMC115068] [PubMed: 11483769]
  86. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965. [PubMed: 11583749]
  87. McKeating JA, Zhang LQ, Logvinoff C, Flint M, Zhang J, Yu J, Butera D, Ho DD, Dustin LB, Rice CM, Balfe P. Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner. J Virol. 2004;78:8496–8505. [PMC free article: PMC479078] [PubMed: 15280458]
  88. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, Strathdee SA, Vlahov D, Thomas DL. Protection against persistence of hepatitis C. Lancet. 2002;359:1478–1483. [PubMed: 11988247]
  89. Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol. 2002;2:957–964. [PubMed: 12461568]
  90. Morishima C, Musey L, Elizaga M, Gaba K, Allison M, Carithers RL, Gretch DR, McElrath MJ. Hepatitis C virus-specific cytolytic T cell responses after antiviral therapy. Clin Immunol. 2003;108:211–220. [PubMed: 14499244]
  91. Moutaftsi M, Mehl AM, Borysiewicz LK, Tabi Z. Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood. 2002;99:2913–2921. [PubMed: 11929782]
  92. Navas MC, Fuchs A, Schvoerer E, Bohbot A, Aubertin AM, Stoll-Keller F. Dendritic cell susceptibility to hepatitis C virus genotype 1 infection. J Med Virol. 2002;67:152–161. [PubMed: 11992576]
  93. Nuti S, Rosa D, Valiante N M, Saletti G, Caratozzolo M, Dellabona P, Barnaba V, Abrignani S. Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Valpha24+ T cells and rapid elimination of effector cells by apoptosis. Eur J Immunol . 1998;28:3448–3455. [PubMed: 9842887]
  94. Park S, Murray D, John B, Crispe IN. Biology and significance of T-cell apoptosis in the liver. Immunol Cell Biol. 2002;80:74–83. [PubMed: 11869364]
  95. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 2003;299:1033–1036. [PubMed: 12532024]
  96. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med. 2002;195:335–341. [PMC free article: PMC2193592] [PubMed: 11828008]
  97. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding of hepatitis C virus to CD81. Science. 1998;282:938–941. [PubMed: 9794763]
  98. Pohlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G, Granelli-Piperno A, Doms RW, Rice CM, McKeating JA. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol. 2003;77:4070–4080. [PMC free article: PMC150620] [PubMed: 12634366]
  99. Raftery MJ, Schwab M, Eibert SM, Samstag Y, Walczak H, Schonrich G. Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity. 2001;15:997–1009. [PubMed: 11754820]
  100. Rehermann B, Chisari FV. Cell mediated immune response to the hepatitis C virus. Curr Top Microbiol Immunol. 2000;242:299–325. [PubMed: 10592666]
  101. Rinaldo CR Jr, Piazza P. Virus infection of dendritic cells: portal for host invasion and host defense. Trends Microbiol. 2004;12:337–345. [PubMed: 15223061]
  102. Rollier C, Drexhage JA, Verstrepen BE, Verschoor EJ, Bontrop RE, Koopman G, Heeney JL. Chronic hepatitis C virus infection established and maintained in chimpanzees independent of dendritic cell impairment. Hepatology. 2003;38:851–858. [PubMed: 14512872]
  103. Rosen HR, Miner C, Sasaki AW, Lewinsohn DM, Conrad AJ, Bakke A, Bouwer HG, Hinrichs DJ. Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages. Hepatology. 2002;35:190–198. [PubMed: 11786976]
  104. Sabile A, Perlemuter G, Bono F, Kohara K, Demaugre F, Kohara M, Matsuura Y, Miyamura T, Brechot C, Barba G. Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates. Hepatology. 1999;30:1064–1076. [PubMed: 10498661]
  105. Sarobe P, Lasarte JJ, Zabaleta A, Arribillaga L, Arina A, Melero I, Borras-Cuesta F, Prieto J. Hepatitis C virus structural proteins impair dendritic cell maturation and inhibit in vivo induction of cellular immune responses. J Virol. 2003;77:10862–10871. [PMC free article: PMC224971] [PubMed: 14512536]
  106. Schneider-Schaulies S, Klagge IM, ter Meulen V. Dendritic cells and measles virus infection. Curr Top Microbiol Immunol. 2003;276:77–101. [PubMed: 12797444]
  107. Servet-Delprat C, Vidalain PO, Valentin H, Rabourdin-Combe C. Measles virus and dendritic cell functions: how specific response cohabits with immunosuppression. Curr Top Microbiol Immunol. 2003;276:103–123. [PubMed: 12797445]
  108. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002;2:389–400. [PubMed: 12093005]
  109. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005;41:771–778. [PubMed: 15791617]
  110. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology. 2003;38:1437–1448. [PubMed: 14647055]
  111. Sun J, Bodola F, Fan X, Irshad H, Soong L, Lemon SM, Chan TS. Hepatitis C virus core and envelope proteins do not suppress the host's ability to clear a hepatic viral infection. J Virol. 2001;75:11992–11998. [PMC free article: PMC116094] [PubMed: 11711589]
  112. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A, Miller JL, Manns MP, Rehermann B. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med. 2000;6:578–582. [PubMed: 10802716]
  113. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999;285:107–110. [PubMed: 10390359]
  114. Tellinghuisen TL, Rice CM. Interaction between hepatitis C virus proteins and host cell factors. Curr Opin Microbiol. 2002;5:419–427. [PubMed: 12160863]
  115. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194:1395–1406. [PMC free article: PMC2193681] [PubMed: 11714747]
  116. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002;195:43–49. [PMC free article: PMC2196015] [PubMed: 11781364]
  117. Tsubouchi E, Akbar SM, Horiike N, Onji M. Infection and dysfunction of circulating blood dendritic cells and their subsets in chronic hepatitis C virus infection. J Gastroenterol. 2004a;39:754–762. [PubMed: 15338369]
  118. Tsubouchi E, Akbar SM, Murakami H, Horiike N, Onji M. Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy. Clin Exp Immunol. 2004b;137:417–423. [PMC free article: PMC1809112] [PubMed: 15270861]
  119. Ulsenheimer A, Gerlach JT, Gruener NH, Jung MC, Schirren CA, Schraut W, Zachoval R, Pape GR, Diepolder HM. Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C. Hepatology. 2003;37:1189–1198. [PubMed: 12717401]
  120. Vertuani S, Bazzaro M, Gualandi G, Micheletti F, Marastoni M, Fortini C, Canella A, Marino M, Tomatis R, Traniello S, Gavioli R. Effect of interferon-alpha therapy on epitope-specific cytotoxic T lymphocyte responses in hepatitis C virus-infected individuals. Eur J Immunol. 2002;32:144–154. [PubMed: 11754355]
  121. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–979. [PMC free article: PMC2211881] [PubMed: 15067033]
  122. Viscidi RP, Mayur K, Lederman HM, Frankel AD. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science. 1989;246:1606–1608. [PubMed: 2556795]
  123. Wang J, Holmes TH, Cheung R, Greenberg HB, He XS. Expression of chemokine receptors on intrahepatic and peripheral lymphocytes in chronic hepatitis C infection: its relationship to liver inflammation. J Infect Dis. 2004;190:989–997. [PubMed: 15295707]
  124. Ward SM, Jonsson JR, Sierro S, Clouston AD, Lucas M, Vargas AL, Powell EE, Klenerman P. Virus-specific CD8+ T lymphocytes within the normal human liver. Eur J Immunol. 2004;34:1526–1531. [PubMed: 15162421]
  125. Watanabe T, Yoshida M, Shirai Y, Yamori M, Yagita H, Itoh T, Chiba T, Kita T, Wakatsuki Y. Administration of an antigen at a high dose generates regulatory CD4+ T cells expressing CD95 ligand and secreting IL-4 in the liver. J Immunol. 2002;168:2188–2199. [PubMed: 11859105]
  126. Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH, Liang TJ, Alter H, Rehermann B. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol. 2002;169:3447–3458. [PubMed: 12218168]
  127. Wertheimer AM, Bakke A, Rosen HR. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology. 2004;40:335–345. [PubMed: 15368438]
  128. Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004;78:5535–5545. [PMC free article: PMC415833] [PubMed: 15140950]
  129. Yao ZQ, Eisen-Vandervelde A, Ray S, Hahn YS. HCV core/gC1qR interaction arrests T cell cycle progression through stabilization of the cell cycle inhibitor p27Kip1. Virology. 2003;314:271–282. [PubMed: 14517080]
  130. Yao ZQ, Eisen-Vandervelde A, Waggoner SN, Cale EM, Hahn YS. Direct binding of hepatitis C virus core to gC1qR on CD4+ and CD8+ T cells leads to impaired activation of Lck and Akt. J Virol. 2004;78:6409–6419. [PMC free article: PMC416530] [PubMed: 15163734]
  131. Yao ZQ, Nguyen DT, Hiotellis AI, Hahn YS. Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. J Immunol. 2001;167:5264–5272. [PubMed: 11673541]
  132. Zhang J, Randall G, Higginbottom A, Monk P, Rice CM, McKeating JA. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J Virol. 2004;78:1448–1455. [PMC free article: PMC321402] [PubMed: 14722300]
  133. Zitvogel L. Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med. 2002;195:F9–14. [PMC free article: PMC2193597] [PubMed: 11828015]
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