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(Journal of Leukocyte Biology. 2009;85:205-214.)
© 2009 Society for Leukocyte Biology

Modulation of dendritic cell function by persistent viruses

Bisheng Liu, Andrea M. Woltman, Harry L. A. Janssen and Andre Boonstra1

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

1 Correspondence: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, s-Gravendijkwal 230, Room L-455, 3015 CE Rotterdam, The Netherlands. E-mail: p.a.boonstra{at}erasmusmc.nl


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ABSTRACT
 
Worldwide, chronic viral infections cause major health problems with severe morbidity and mortality. HIV and hepatitis C virus (HCV) manifest themselves as persistent infections, but they are entirely distinct viruses with distinct replication mechanisms, tropism, and kinetics. Coinfections with HCV among people with HIV are emerging as a growing problem. Cellular immune responses play an important role in viral clearance and disease pathogenesis. However, cellular immunity to HIV and HCV is affected severely in chronic patients. Various hypotheses have been proposed to explain the dysfunctional T cell response, including viral escape mutations, exhaustion of the T cell compartment, and the activity of regulatory T cells. Also, modulation of the function of dendritic cells (DC) has been suggested as one of the mechanisms used by persistent viruses to evade the immune system. In this review, we will focus on DC interactions with one murine persistent virus (lymphocytic choriomeningitis virus clone 13) and two human persistent viruses (HIV-1 and HCV), intending to examine if general strategies are used by persistent viruses to modulate the function of DC to improve our understanding of the mechanisms underlying the development and maintenance of viral persistence.

Key Words: LCMV • HIV • HCV • hepatitis • immune evasion


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INTRODUCTION
 
Viral infection initiates a series of events that may culminate in the generation of an effective immune response capable of eliminating the virus. The immune response to viral infection relies on the combined action of the innate and adaptive immune system. The innate immune system, which involves dendritic cells (DC), NK cells, complement, and cytokines, is the first response to various viral infections prior to the appearance of the adaptive or virus-specific immune response, mediated by T or B cells. Because of their extraordinary features, DC fulfill a special role in the immune system [1 2 3 ]. They originate from the bone marrow and migrate through blood to secondary lymphoid organs and tissue. DC operate at the interface between the innate and adaptive immune response by their ability to sample their environment for pathogenic products, to process them, and to present viral antigens to T cells [4 ]. This results in T cell proliferation and the induction of virus-specific adaptive immune responses.

Th1 cells produce IFN-{gamma} and play a central role in cell-mediated immunity [5 6 7 ]. The development of Th1 cells can be promoted through the activation of distinct populations of DC via the production of IL-12p70 and in some cases, IFN-{alpha} [8 9 10 11 12 13 ]. The activation of DC relies on its expression of numerous pathogen recognition receptors (PRRs), such as C-type lectins and TLRs, which recognize molecular patterns expressed by pathogens, such as LPS, RNA, or DNA sequences [14 15 16 ]. These microbial stimuli induce significant morphological and biochemical changes in DC, such as enhanced secretion of TNF, IL-6, IL-12, IL-10, and IFN-{alpha}, and increased expression on DC of MHC and costimulators, including CD80, CD86, and CD40. This activation of DC is required for efficient priming of pathogen-specific T cells.

Human DC have been categorized into two major subsets: CD11c+ myeloid DC and CD11c– CD123+ plasmacytoid DC [17 18 19 20 ]. They have been shown to express different TLR and consequently. respond to distinct microbial products (Fig. 1 ). For example, human myeloid DC express TLR3 and respond to the TLR ligand polyinosinic:polycytidylic acid [poly(I:C)] by producing IL-12p70, which promotes Th1 cell development [21 ]. Myeloid DC are considered classical APCs, as they are able to initiate the activation of naïve and effector T cells. Because of the low numbers of myeloid DC in blood, DC generated from peripheral blood monocytes, in the presence of IL-4 and GM-CSF, have been used extensively [22 ]. These cells share some but not all features of blood myeloid DC. It is unclear whether a counterpart of monocyte-derived DC is circulating in the body, but it has been suggested that these cells represent inflammation-induced tissue myeloid DC [23 ]. Plasmacytoid DC, on the other hand, are best known for their extraordinary ability to secrete high levels of IFN-{alpha} in response to ligation of TLR7 and TLR9 and by bacterial and viral RNA or DNA [21 , 24 ]. Plasmacytoid DC exert strong antiviral effects mediated via IFN-{alpha}, as has been reported in a number of viral infections [24 , 25 ]. However, they are poor inducers of T cell proliferation as a result of their low efficiency in capturing, processing, and loading antigen onto MHC molecules and their weak expression of costimulators [26 ].


Figure 1
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  		Figure 1. Human myeloid DC and plasmacytoid DC (pDC) express different TLR and consequently respond to distinct microbial stimuli. IL-12 production by myeloid DC can be stimulated by a large range of microbial products and augmented by CD40 ligation or cytokines such as IFN-{gamma}, resulting in the development of Th1 cells. Cytokines, such as IL-10, negatively regulate the production of IL-12. Activated plasmacytoid DC produce large amounts of IFN-{alpha}, which has potent antiviral activity.

The activation of DC and subsequent cytokine production, such as IL-12p70 and IFN-{alpha}, are highly regulated by positive- and negative-feedback mechanisms. For instance, positive regulation is achieved by additional CD40 ligation and the presence of IFN-{gamma}, which are signals normally provided by T cells [27 ]. On the other hand, anti-inflammatory cytokines, such as IL-10, strongly inhibit the expression of IL-12p70 and IFN-{alpha}, as well as suppress the production of other proinflammatory cytokines [27 , 28 ]. This negative regulation may be important to prevent excessive DC and T cell activation, which might result in pathology but at the same time, may limit the efficacy of the ongoing immune response against pathogens, thereby allowing pathogen survival.

When antiviral responses are insufficient, the host and the virus may establish some form of long-term relationship, i.e., viral persistence, as observed following infections with HIV and hepatitis C virus (HCV). As DC bridge innate and adaptive responses, exploitation of DC by the virus is an effective strategy to disrupt the host immune response by impairing DC function and as a consequence, achieving persistent infection. In this review, we will discuss if distinct, persistent viruses indeed exploit DC to promote the development of chronic infections. Integration of our knowledge about the immune evasion mechanisms used by a murine persistent virus [lymphocytic choriomeningitis virus variant (LCMV; clone 13] and two distinct human persistent viruses (HIV-1 and HCV) indicates that a number of similar strategies are used by these unrelated viruses to modulate the function of DC.


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LCMV, A MURINE RNA VIRUS
 
Over the last decade, detailed insight has been obtained in the immunological mechanisms that are involved in the establishment and maintenance of various persistent viral infections. Most of this knowledge is derived from studies in mice, in which infections with LCMV, a murine, ambisense RNA virus, are considered the prototype for viral persistent infections [29 ]. The outcome of infection of mice with the LCMV Armstrong strain is resolution of the infection. Following inoculation, a sharp increase in viral levels is observed for 3–4 days, which declines soon afterwards until the virus is cleared completely. Clearance of the LCMV Armstrong strain is mediated by a strong adaptive immune response, characterized by proliferation and activation of highly effective, LCMV-specific CD4+ and CD8+ T cells [30 31 32 ]. In contrast, infection with LCMV variant clone 13 in mice displays all of the features of a persistent viral disease, and high viral titers are observed months after inoculation [33 , 34 ]. Importantly, in mice persistently infected with LCMV clone 13, a generalized immunosuppression is observed, characterized by ablation of specific T cell responses to multiple viruses, as well as antibody responses to many different antigens [34 , 35 ]. Immunosuppression in mice infected by LCMV clone 13 appears to result from a defect in antigen presentation, rather than from a direct effect on T cells and B cells, as demonstrated by adoptive transfer experiments [34 35 36 ].

Macrophages, stromal cells, and DC can all be infected by LCMV
The receptor for LCMV is {alpha}-dystroglycan [37 ], which is a cellular receptor for extracellular matrix proteins. Importantly, it was found that persistent LCMV strains, such as LCMV clone 13, bind {alpha}-dystroglycan with higher affinity than LCMV Armstrong [37 ]. A 2- to 3-log difference in binding affinity was observed for LCMV strains that caused a persistent infection as compared with strains that did not [38 ], which could be mapped to a single amino acid change in the viral glycolipid-1 ligand that binds {alpha}-dystroglycan [38 ]. The high dependency of persistent LCMV strains on {alpha}-dystroglycan most likely leads to their preferential infection of splenic CD11c+ and DEC205+ DC in the marginal zone and white pulp of the spleen [34 , 38 ]. Three weeks following LCMV infection, the majority of splenic DC is infected. On the other hand, LCMV strains that do not cause persistent infections mainly infect macrophages and few DC in the red pulp, most likely because they are less dependent on {alpha}-dystroglycan for infection [34 , 38 , 39 ]. In addition, LCMV clone 13 but not LCMV Armstrong can infect the majority of hematopoietic progenitors from bone marrow, rendering them unresponsive to fetal liver tyrosine kinase 3 ligand and GM-CSF in vivo and in vitro. As a consequence of LCMV clone 13 infection of hematopoietic progenitors, the development of CD8{alpha}+ and CD8{alpha}– DC is impaired [40 ], which was found to require IFN-{alpha}/β but was not via induction of apoptosis of DC [38 ]. Interestingly, it was reported previously that LCMV clone 13-infected DC but not Armstrong-infected DC induced the secretion of IFN-{alpha}/β [41 ]. Thus, infection with LCMV clone 13 but not LCMV Armstrong leads to reduced numbers of DC within the host, which may explain the difference in disease outcome. In addition, infection of DC with LCMV clone 13 but not LCMV Armstrong renders LCMV clone 13-infected DC as targets for the cytotoxic activity of LCMV-specific CD8+ T lymphocytes, resulting in a further reduction of DC numbers [34 ].

Splenic CD11c+ DC isolated from mice infected with LCMV clone 13 demonstrated a markedly inhibited expression of MHC class I, MHC class II, CD40, CD86, and CD80 molecules, which was not observed for DC from LCMV Armstrong-infected mice [40 ]. Interestingly, reduced expression of the costimulators MHC class II, CD80, and CD86 was still observed at Day 120, when LCMV clone 13-infected mice had controlled the infection, whereas the expression of CD40 and MHC class I had recovered completely at that time. Therefore, control of the infection and the recovery of the costimulatory ability of DC do not correlate in time. At Day 360 after infection, the expression of all costimulators had recovered completely. As a result of the reduced expression of costimulators during clone 13 infection, DC were unable to induce T cell proliferation efficiently in a primary, allogeneic MLR [34 , 38 ]. These results indicate that LCMV clone 13 specifically targets DC, which may render them ineffective to stimulate T cells and ultimately lead to immunosuppression.

Besides an effect on the levels of costimulators, LCMV also modulates cytokine production by DC. IL-12, produced by DC, is a key factor in promoting the development of IFN-{gamma}-producing Th1 cells. However, in LCMV infections, the development of Th1 responses appears to be independent of IL-12, as the cytokine secretion profile of LCMV-specific CD4+ T cells in IL-12-deficient mice was identical to normal mice [42 , 43 ]. Instead, under normal conditions, LCMV-specific IFN-{gamma} responses by CD8+ T cells were mediated via IFN-{alpha}/β, as demonstrated using IFN-{alpha}/βR knockout mice [42 ]. Lack of IFN-{alpha}/β resulted in enhanced IL-12 production, demonstrating negative-feedback mechanisms controlling IL-12 production. In this situation, the LCMV viral titers were increased, demonstrating the superior effect of type I IFN over IL-12 in inhibiting viral replication [42 ]. The source of IFN-{alpha}/β in response to LCMV remains controversial. Following LCMV Armstrong infection, a rapid increase of the numbers of plasmacytoid DC as well as up-regulation of IFN-{alpha} expression were observed in the spleen [44 ]. Using IFN-{alpha}-GFP reporter mice, it was reported recently that plasmacytoid DC are indeed responsible for high MyD88-dependent IFN-{alpha} production following infection [45 ]. However, depletion of plasmacytoid DC in vivo did not affect IFN-{alpha}/β levels in serum during LCMV Armstrong infection [46 ]. Moreover, nonplasmacytoid DC from mice infected with LCMV have also been shown to produce high IFN-{alpha} levels [41 ].

Distinct production of IFN-{alpha}/β has been implicated in the establishment of persistence to LCMV
Mice infected with LCMV clone 13 demonstrated sustained production of IFN-{alpha}/β by immature and mature DC from the spleen and bone marrow for ~2 months, which was not observed in mice infected with LCMV Armstrong [47 ]. However, LCMV clone 13 infections in mice were less sensitive to IFN-{alpha}/β and IFN-{gamma}, as compared with LCMV Armstrong [48 ]. Studies with mice deficient in the IFN-{alpha}/β pathway revealed that a "resolving" LCMV variant (LCMV-WE) was able to initiate a persistent infection as a result of the absence of virus-specific CD8+ T cells, and clearance of LCMV Armstrong proceeded but with slower kinetics [42 , 49 , 50 ]. Thus, these findings indicate that infection with persistent LCMV strains can subvert the antiviral effect of type I IFN to benefit its own survival, which was, at least in part, by inhibition of the development of the DC compartment in infected mice.

Another important level of regulation of immune responses is mediated by immunosuppressive cytokines, such as IL-10, which suppresses the function of APCs and T cells, mainly via inhibition of proinflammatory cytokine production, costimulation, and MHC class II expression [28 ]. In recent years, it was reported that IL-10 production is increased dramatically in mice infected persistently with LCMV clone 13 as compared with LCMV Armstrong [51 , 52 ]. Brooks et al. [51 ] suggested that DC are the source of IL-10 in persistently infected mice, whereas Ejrnaes et al. [52 ] demonstrated that modulation of the DC compartment results in enhanced IL-10 production by CD4+ T cells. Importantly, both studies showed that neutralization of the activity of IL-10 in mice chronically infected with LCMV clone 13 resulted in restoration of the impaired T cell response and clearance of the virus. The induction of IL-10 by specific strains of the virus or the tendency of the host to produce more IL-10 may contribute to the inability to clear the virus and the development of viral persistence.

Thus, persistent strains of LCMV have evolved multiple strategies for suppressing and altering DC function, thereby reducing the host’s ability to induce adaptive immune responses.


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HIV, A RETROVIRUS
 
Infection with the HIV-1 virus continues to develop as a global pandemic with an estimated 33 million infected individuals and 2.1 million people dying from AIDS in 2007 (http://www.who.int/mediacentre/news/releases/2007/pr61/en/index.html). The hallmark of HIV-1 pathogenesis is the gradual loss of CD4+ T cells throughout chronic disease, ultimately resulting in enhanced susceptibility to opportunistic infections. The progressive depletion of the CD4+ T cell during the chronic stage of infection is most likely a result of direct HIV infection and subsequent cell deletion, as well as activation-induced cell death, as reviewed in ref. [53 ].

At the mucosal site, DC may capture HIV and promote spreading and transmission of the virus. This may lead to delivery of the virus to the lymph nodes, where infection of CD4+ T cells may occur [54 55 56 ]. HIV also infects DC via specific receptors on DC, such as CCR5 and CXCR4 [57 58 59 ]. However, compared with CD4+ T cells, HIV replication in DC is less productive, and the frequency of HIV-infected DC is low as a result of the low level of CXCR4 and CCR5 expression and the activity of fusion restriction factors in DC [60 , 61 ]. Mucosal DC are among the first cellular targets for HIV-1 during sexual transmission [62 63 64 65 66 67 ]. In vitro, Langerhans cells from the skin, vaginal DC, blood myeloid DC, and DC generated from monocytes or CD34+ progenitors can all be infected with HIV [58 , 68 69 70 71 72 73 74 75 76 ]. The maturation status of DC is thought to affect the susceptibility of DC to become infected with HIV. Immature DC are more susceptible to infection, whereas mature DC are more difficult or even resistant to become infected [77 , 78 ].

Numerous studies have examined the role of blood myeloid and plasmacytoid DC in HIV-1 immunopathogenesis. A decrease in the absolute numbers of myeloid DC and plasmacytoid DC in blood of HIV-1-infected donors is observed in most studies [79 80 81 82 83 84 ]. It was suggested that loss of DC in HIV infection may contribute to disease progression, as the depletion is progressive and correlates with HIV-1 plasma viral load [80 , 85 ]. Importantly, asymptomatic long-term survivors had increased numbers of plasmacytoid DC relative to individuals with progressive disease or uninfected controls, suggesting that plasmacytoid DC can protect against disease progression, although the increased numbers can also be the consequence of lower levels of viral replication [85 ]. Moreover, patients undergoing antiretroviral therapy show a recovery of the numbers of plasmacytoid DC [86 ], further suggesting a role for plasmacytoid DC in HIV pathogenesis. There are no indications that HIV-1 inhibits DC progenitor expansion, but depletion of plasmacytoid DC via apoptosis and necrosis in vitro has been reported [87 ]. In addition, disappearance of DC from the circulation has been suggested to be a result of recruitment of cells to lymphoid tissue, as demonstrated on the basis of expression of the CCR7 and CXCR3 migration markers [84 , 88 89 90 ]. In addition, reduced numbers of plasmacytoid DC, as observed in AIDS patients, might be the consequence of opportunistic infections [85 ].

Functionally, less-efficient stimulation by DC of allogeneic T cells was observed when comparing peripheral blood DC of HIV-infected individuals at different stages of infection with DC from healthy donors [82 , 91 , 92 ]. Interestingly, DC infected with HIV-1 in vitro induced IL-10 secretion by T cells, which may explain, at least in part, the reduced T cell response [93 ]. Whereas viruses can generally activate DC by inducing HLA-DR and costimulators, such as CD80, CD86, and CD40, HIV infection of DC neither leads to activation of immature, monocyte-derived DC [93 ] or plasmacytoid DC in vitro [94 ], except when large amounts of virus are added [74 , 93 , 95 ]. Also when exposed to different maturation stimuli, DC infected with HIV-1 failed to become activated. In contrast, HIV viral protein R (vpr) and Nef protein expressed in DC using vaccinia or adenovirus have been found to reduce the levels of CD86, CD80, and HLA-DR on monocyte-derived DC in vitro [96 97 98 99 ]. Coinciding with this reduced expression of costimulators, these DC were impaired in their ability to activate CD8+ T cells.

Modulation of DC-derived cytokine production by HIV, which was observed in most studies, may contribute further to evasion of host immune responses by HIV
Stimulation of PBMC or whole blood from HIV-infected individuals showed reduced production of IL-12 as compared with controls [100 101 102 103 ]. In agreement with this, upon stimulation with a HIV-1 isolate, p24-expressing DC failed to produce IL-12p70 in response to CD40 ligation [104 ]. This may be mediated via the HIV vpr protein, as inhibition of the production of IL-12 and up-regulation of IL-10 production were observed in monocyte-derived DC stimulated in the presence of vpr protein, whereas IL-6 and IL-1β levels were not affected [96 ]. However, adenoviral-encoded Nef in immature DC induced IL-6, IL-12, and TNF production [99 , 105 ], and monocyte-derived DC stimulated in vitro with gp120 from the HIV-1 strain JR-FL induced IL-10 secretion in the majority of donors [106 ]. These distinct and in some cases opposing effects on modulation of DC-derived cytokine production by HIV are likely a result of the use of distinct HIV isolates or HIV components and the use of different sources of DC.

In addition to the reduced numbers of plasmacytoid DC during chronic HIV infection, the capacity to produce IFN-{alpha} was found to be reduced by plasmacytoid DC of these patients [83 , 85 , 86 , 103 ]. This is important, as HIV-induced IFN-{alpha} contributes, at least in part, to the restriction of viral replication in plasmacytoid DC [107 , 108 ] and CD4+ T cells [87 , 109 ], as well as to bystander activation of myeloid DC [89 ]. Plasmacytoid DC directly recognize and respond to HIV-1 infection by inducing maturation and the production of large quantities of IFN-{alpha} [74 , 89 , 107 , 109 110 111 ]. This is in contrast to myeloid DC, which do not mature upon incubation with HIV. There is general consensus that gp120 is required for IFN-{alpha} induction by plasmacytoid DC, which is mediated through its interaction with CD4 [89 , 109 , 111 , 112 ]. However, recently, it was shown that gp120 suppresses CpG-induced activation of plasmacytoid DC, including the production of IFN-{alpha}. This effect was only observed when plasmacytoid DC were stimulated via TLR9, but not via TLR7 [113 ]. On the other hand, it was found that IFN-{alpha} produced by plasmacytoid DC after HIV-1 exposure regulates the expression of TRAIL on CD4+ T cells, resulting in apoptosis of these T cells [114 ].

Similar to persistent LCMV, HIV-1 also inhibits DC activation and modulates the cytokine expression by DC, thereby evading the host immune response. HIV and LCMV have evolved strategies to subvert the function of type I IFN for their own benefits.


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THE HCV, AN RNA VIRUS
 
Worldwide, another viral pathogen that causes major health problems is the HCV, which is not a retrovirus, but an enveloped, positive, single-stranded RNA virus. It is estimated that 80–90% of individuals infected with HCV become chronically infected, and these patients are at increased risk of developing cirrhosis and hepatocellular carcinoma, which may take decades to develop. At present, it is still unclear why some individuals are able to clear the infection spontaneously, whereas others do not. Weak and functionally impaired, HCV-specific T cells responses are a characteristic feature of chronic HCV infection, in common with persistent HBV and LCMV infections [115 116 117 ].

Binding of HCV to hepatocytes involves many receptors that were identified by screening for surface markers that bind the envelope proteins E1 and E2. In this way, CD81, scavenger receptor class B, DC-specific ICAM-grabbing nonintegrin (SIGN), liver/lymph node-SIGN, and the asialoglycoprotein receptor were identified [118 119 120 121 ]. In addition, the low-density lipoprotein receptor, by binding HCV particles associated with lipoprotein, and claudin-1, a tight-junction component highly expressed in the liver, are involved in viral binding and/or entry [122 ]. The involvement of these diverse proteins in HCV cell entry suggests multiple pathways or a complex series of sequential steps for viral entry. The primary site of infection of HCV is the liver, and replication can take place in hepatocytes. However, HCV RNA has also been detected in extrahepatic locations, including cells of the lymphatic system (PBMC), bone marrow, and the CNS [123 , 124 ]. Although there is still debate, numerous studies have reported the presence of positive-strand HCV RNA and importantly, its replicative, intermediate-negative strand HCV RNA in peripheral blood DC following infection in vitro or directly ex vivo [125 126 127 128 129 ]. However, the frequency of DC containing HCV RNA and the levels of the virus in DC are extremely low [125 , 126 ]. The scavenger receptor B1 has been shown recently to be required for not only binding but also the uptake of HCV and cross-presentation by human DC [130 ]. At present, no information is available as to whether other receptors on DC can perform similar activities.

Similar to LCMV and HIV-1 infection, in patients with chronic HCV infections, decreased frequencies of peripheral myeloid DC and plasmacytoid DC have been demonstrated in the majority of studies [127 , 131 132 133 134 135 136 137 138 139 ]. However, similar as described for HIV, it is possible that altered frequencies of peripheral DC may be a consequence of migration toward the site of infection, and therefore, peripheral numbers do not necessarily mirror the capacity of the DC compartment in chronic HCV patients. For this, it is preferable to monitor DC numbers and their function in the liver, but to date, only few studies have examined intrahepatic DC in HCV infections [139 ]. Using immunohistochemistry, it was shown that the numbers of myeloid and plasmacytoid DC in the livers of patients with chronic HCV were increased markedly, as compared with normal control specimens [139 ]. However, it is difficult to determine if accumulation of DC in the liver is causally related to the decrease of DC numbers in peripheral blood. Another possibility is that HCV targets DC precursors as reported by Sansonno et al. [140 ] or that HCV targets DC directly to reduce their numbers. In this regard, it has been shown that HCV core NS3 and NS5 proteins all induce apoptosis in mature DC in vitro [141 ].

Besides reduced numbers of myeloid DC, it was found that myeloid DC from chronic HCV patients showed a decrease in their capacity to stimulate allogeneic T cells [131 , 142 , 143 ]. Also, with respect to the levels of costimulators expressed on peripheral blood myeloid DC from chronic HCV patients as compared with healthy controls, reduced expression of HLA-DR and CD86 was observed by some [142 ] but not all studies [134 , 144 ]. Interestingly, Tsubouchi et al. [127 ] found that successful therapy with IFN-{alpha} and ribavirin increased the expression of costimulators on myeloid DC and increased their allostimulatory capacity when DC were examined before and 4 weeks after therapy. Clearly, more studies with larger cohorts of patients need to be performed to resolve this issue.

In chronic HCV patients, myeloid DC were found to produce less IL-12 in response to stimuli, such as poly(I:C) or CD40 ligand, whereas the production of the anti-inflammatory cytokine IL-10 was enhanced [103 , 131 , 142 , 143 , 145 146 147 ]. The reduced IL-12p70 production by DC could be restored following successful antiviral therapy of chronic HCV patients, suggesting that the presence of HCV specifically inhibits the activity of DC [127 ]. Although Longman et al. [148 ] reported normal phenotypic characteristics and allogeneic functions in monocyte-derived DC, the majority of researchers found that monocyte-derived DC of patients with chronic HCV infections displayed a less-mature phenotype and had an impaired allostimulatory capacity [125 , 135 , 149 , 150 ].

To date, the mechanisms whereby HCV affects DC function remain largely elusive. It is possible that HCV proteins play a role in suppressing protective immunity through interactions with host immune cells, such as DC. Indeed, the HCV core protein has been reported to impair the function of DC [151 152 153 154 155 ]. Mouse myeloid DC treated with HCV core-expressing plasmid had a reduced surface expression of MHC I, MHC II, CD80, CD86, and programmed death ligand-1, and associated with this was an impaired in vitro priming of CD4+ T cells [155 ]. HCV core protein was also able to selectively inhibit TLR4-induced IL-12 production after interacting with the gC1q receptor on the surface of monocyte-derived DC by activating the PI-3K pathway, leading to reduced Th1 cell development [151 , 154 ]. Besides the HCV core protein, also, suppressed T cell responses were described as a result of the effect of NS3 and NS4 on monocytes or DC [156 , 157 ].

Further indications that HCV affects DC function came directly from studies using the recently described cell culture-grown HCV (HCVcc). Culture with HCVcc demonstrated inhibition of maturation of monocyte-derived DC induced by a cocktail of cytokines (IL-1β, TNF, IL-6, PGE2) while enhancing the production of IL-10. In addition, DC exposed to HCVcc were impaired in their ability to stimulate antigen-specific T cell responses [158 ]. In contrast, similar experiments performed by Shiina and Rehermann [159 ] found no inhibition of maturation induced by LPS or poly(I:C) nor affected cytokine production of blood myeloid DC and monocyte-derived DC or T cell proliferation in a MLR response. The distinct maturation stimuli used, different doses of HCVcc, or differences in the HCVcc itself might explain the conflicting findings reported by these studies. Thus, although individual HCV proteins have been shown to modulate the function of DC in vitro, more studies need to be conducted to determine the immunomodulatory effect of the complete HCV virus on DC function.

Numerous studies have also reported on an impairment of the function of plasmacytoid DC from blood of HCV patients as compared with healthy controls, as demonstrated by reduced production of IFN-{alpha} upon stimulation with herpes simplex virus or TLR ligands [103 , 131 , 132 , 137 , 142 , 159 160 161 ]. Importantly, patients who resolved their HCV infection spontaneously and patients who responded to therapy showed similar numbers of plasmacytoid DC and IFN-{alpha} production as healthy control individuals [132 , 138 ]. Interestingly, Dolganiuc et al. [138 ] demonstrated in vitro that in response to HCV core protein, monocyte-derived TNF and IL-10 were responsible for the reduction of IFN-{alpha} production by plasmacytoid DC. The limited number of studies that examined the consequence of HCV infection on the ability of plasmacytoid DC to stimulate T cells found reduced activation of CD4+ T cells [131 , 161 ]. Although the majority of studies supports the observations that the plasmacytoid DC are impaired, others demonstrated that on a per-cell basis, IFN-{alpha} production by plasmacytoid DC is similar to healthy controls [132 , 134 ]. Also, the effect of exposure of plasmacytoid DC to cell culture-produced HCVcc is still unclear, as inhibition of IFN-{alpha} production in a dose-dependent manner was reported [159 ], as well as no effect on plasmacytoid DC, as determined by a broad array of cytokines and chemokines [162 ].

In recent years, it has been shown that HCV is efficient in interfering with IFN signaling at multiple levels. Multiple HCV proteins were capable of selectively degrading STAT-1 and reducing accumulation of phosphorylated STAT-1 in the nucleus [163 ], resulting in a reduced capacity to stimulate IFN target genes. In addition, specific molecules of signaling pathways, activated upon recognition of viral RNA, such as Toll/IL-1R domain-containing adaptor-inducing IFN-β and Cardif, are targeted by the HCV NS3 and NS4 proteins (reviewed in ref. [164 ]). Disruption of these signaling pathways may be a critical mechanism of HCV to reduce type I IFN responses and thus, potently disrupt the antiviral response.

Together, the reduced frequency of myeloid DC and plasmacytoid DC, reduced IL-12 and IFN-{alpha}, and increased IL-10 production, accompanied by an impaired capacity to prime naïve T cells, may contribute to the insufficient immune response to HCV in chronic HCV patients. Different from infections with LCMV or HIV-1, viral proteins seem to play a more important role in evading the host immune response to HCV.


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CONCLUDING REMARKS
 
LCMV, HIV, and HCV are highly distinct viruses. From a clinical point of view, the only feature these viruses have in common is their ability to establish persistent infections in the host. Infections with LCMV, HIV, and HCV all demonstrate that DC cannot stimulate T cell responses as efficiently as DC from healthy control individuals. As described in this review, there are many indications that these viruses modulate DC frequencies or function, but the molecular and viral factors responsible are still poorly defined. Although difficult to prove, especially for human viruses, it is highly likely that reduced numbers of DC or altered DC function contribute to the development of weaker antiviral T cell responses. Moreover, to determine if this in turn leads to viral persistence is even more difficult to prove. Reversal of virus-induced modulation of the DC compartment by therapeutic intervention is the only way to determine a causal role for DC in the induction and maintenance of viral persistence. However, at present, no such approaches have been tested in patients.

LCMV clone 13 infection in mice leads to infection and subsequent deletion of DC progenitors, resulting in a reduced number of peripheral DC. For HIV and HCV infection, also, reduced numbers of peripheral DC have been described, but this is most likely a result of altered migration of DC from peripheral blood to lymphoid organs, as has been described for plasmacytoid DC during HIV infection [84 , 89 , 90 ], or tissue.

Most studies demonstrate that infection with LCMV, HCV, and HIV in vivo "produces" a DC with a diminished capacity to activate T cells. Besides affecting activation and maturation of DC, also, altered cytokine production might underlie the limited ability to stimulate the adaptive immune response. In this, all three viruses have evolved ways to undermine the potent, antiviral type I IFN response by disturbing intracellular signaling downstream of the IFNR and PRRs or by affecting survival of DC and CD8+ T cells. In addition, the recent finding that neutralization of DC-derived IL-10 was able to resolve persistent LCMV infection, leading to complete cure of the infected mice [51 , 52 ], demonstrates another important role for DC-derived cytokines in the establishment of persistence. Although enhanced IL-10 production has been described by DC stimulated with viral products from HIV and HCV, and blockade of the IL-10/IL-10R pathway in vitro enhanced CD4+ T cell responses in samples from chronic HIV or HCV patients [165 , 166 ], no in vivo trials to block the activity of IL-10 have been conducted in humans.

These findings showing that the DC compartment is functionally affected in chronic viral infections, as discussed in this review, support the rationale for the development of DC-based strategies for the prevention and treatment of chronic virus infections. In a preliminary study, therapeutic DC vaccination for chronic HIV-1 infection using monocyte-derived DC loaded with inactivated HIV-1 has been shown to reduce the viral load while enhancing the HIV-specific T cell response [167 ]. Also, numerous groups are currently exploring the use of therapeutic manipulation of the innate immune system using TLR agonists for treatment of chronic HIV and HCV infections (reviewed in ref. [168 ]). Restoring the impaired DC compartment may represent a powerful strategy for the treatment of chronic HIV and HCV infection.

Received April 15, 2008; revised September 1, 2008; accepted September 2, 2008.


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A M Woltman, A Boonstra, and H L A Janssen
Dendritic cells in chronic viral hepatitis B and C: victims or guardian angels?
Gut, January 1, 2010; 59(01): 115 - 125.
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