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Chapter 14
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.
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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
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Does HCV Cause Dysfunction in the Immune Cells?
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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.
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Does HCV Cause Dysfunction in the Immune Cells?
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).
Several groups have reported dysfunction of DCs that may potentially affect
adaptive immunity in patients with persistent HCV infection, using various in vitro
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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).
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Does HCV Cause Dysfunction in the Immune Cells?
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.
405
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Does HCV Cause Dysfunction in the Immune Cells?
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.
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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).
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Does HCV Cause Dysfunction in the Immune Cells?
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.
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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.
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Does HCV Cause Dysfunction in the Immune Cells?
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