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The differential immune responses during HBV and HCV infection: mechanisms of the diseases and response
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Hepatology July 2003, Vol 38, Number 1
Antonio Bertoletti1, Carlo Ferrari2. 1Institute of Hepatology, University College London, Royal Free and University College of London Medical School, London, UK; and the 2Divisione Malattie Infettive ed Epatologia, Azienda Ospedaliera di Parma, Parma, Italy.
The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge.
Hepatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide.1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection.3-16 These responses are stronger than those found in patients with chronic infection.17-21 Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity.2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found,23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8+ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection.24 These results have been confirmed by recent reports showing that expansion of interferon (IFN-)+, CD8+, and CD4+ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man10 and in HCV-infected chimpanzees.25 Similar findings have been reported in animal models of HBV infection26 and in patients studied during the incubation phase of HBV infection,27 in whom reduced early expansion of virus-specific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8+ T cells in HBV control has been confirmed further by CD8+ T-cell deletion experiments performed in HBV-infected chimpanzees.28
The humoral immune response plays also an essential role during HBV and HCV infections. HBV and HCV clearances are associated temporally with production of anti-envelope antibodies29,30 and sera with high levels of antiviral antibodies (specific for the viral envelope) can prevent HBV31 and HCV32 infections. Therefore, the integrated activation of both the cellular and humoral arms of the adaptive immune response appears to ultimately allow control of both infections. The different components of the adaptive immune system are so interconnected that the failure of one of them clearly affects the expansion and protective efficacy of the others. Lack of CD4+ T-cell help can impair CD8+ T-cell activity and antibody production,33 whereas the inability to mount a virus-specific CD8+ T-cell response results in a level of circulating virus that cannot be cleared by antibodies alone.34 Thus, instead of making an artificial hierarchy of the most important protective arms of the immune response, we will try to dissect the mechanisms that regulate the induction of a fully integrated innate and adaptive immune response from the early stages of HBV and HCV infection.
Profiles of adaptive immune responses early after HBV and HCV infections
The viral and immunologic events that occur in the first weeks after HBV and HCV infections are likely to influence substantially the final outcome of infection. Nevertheless, a comprehensive immunologic analysis during this period has been performed so far in a very limited number of patients.10,27,35 In addition, the study of the CD8-mediated T-cell response has been restricted to few immunodominant epitopes.10,27 Despite these limitations, it is interesting to note that available studies in human and animal models of HBV and HCV infection appear to be consistent with the interpretation that HBV and HCV are ignored by the adaptive immune response for about 2 months after primary infection. After needle-stick exposure to HCV-positive blood, patients who subsequently controlled the infection showed antiviral-specific CD8+ and CD4+ T-cell responses only after 7 to 10 weeks from exposure.10
The appearance of HBV-specific CD8+ and CD4+ T cells during the incubation time of acute hepatitis B follows the same pattern.27 Activation of the virus-specific cellular immunity is followed by the humoral response, which appears at least 10 to 12 weeks after HBV36 and HCV37 infections. These data are in line with results obtained in animal models. During primary HCV infection of chimpanzees, virus-specific antibody responses are detectable 8 to 12 weeks after infection and HCV-specific T-cell responses appear with identical delays.25,38-41 This long interval of time between infection and induction of the adaptive immunity to HBV and HCV seems to contrast with the reported kinetics of virus-specific T-cell responses to other virus infections. Although comparison of different studies must be interpreted with caution because of possible sensitivity variations in the assays, it is intriguing that although T-cell responses to simian immunodeficiency virus, human immunodeficiency virus, and cytomegalovirus already can be detectable 2 weeks after infection,42,43 this finding is only occasional in HCV-infected chimpanzees because only 10 of the 12 animals reported in the literature24,25,38-41 showed a clear HCV-specific T-cell response by 4 weeks after infection.
The pathogenetic implications of the apparent delay of virus-specific adaptive immune responses are likely to be different in HCV and HBV infections. The methods used for viral quantification are often different, implying a careful interpretation of the results, yet available data appear to be consistent with a different kinetic pattern of HBV and HCV replication (see Fig. 1). While HCV-RNA levels increase rapidly in the first few days of HCV infection,10,25,38,41,44 HBV-DNA and HBV antigens are not detectable in serum and liver for about 4 to 7 weeks after HBV infection,36,45,46 even using methods with a level of sensitivity comparable with the ones used for HCV detection.28 Thus, in HCV infection the adaptive response seems to really ignore for several weeks a substantial quantity of virus (at least 106 copies/mL), whereas the limited quantity of HBV antigens in the early phases of HBV infection is likely responsible for the delayed induction of the HBV-specific adaptive immunity.
In addition to the late detection, quantitative and functional defects of the adaptive immune responses are present during primary HBV and HCV infections. The peak frequency of HBV-specific CD8+ T cells during the acute phase of disease in patients with self-limited infections generally does not exceed 1% of circulating CD8+ T cells.47 Higher frequencies (up to 7% of CD8+ T cells) have been observed in acute HCV-infected patients, but most of these cells show impaired production of IFN-, low perforin content and defective capacity for expansion, and lysis of target cells.16,48 These functional defects are detectable in the acutely infected population, irrespective of the subsequent outcome toward recovery or chronic viral persistence, and are transient only in patients who succeed in clearing the virus spontaneously.48-50
Interestingly, CD8+ T-cell frequencies in patients acutely infected with HCV and HBV are generally lower than those observed during acute Epstein-Barr virus or human immunodeficiency virus infections, where virus-specific IFN--producing CD8+ T cells easily can represent up to 10% of the circulating CD8+ T-cell population, with some cases in which single epitope-specific CD8+ T cells can account for more than 40% of the total CD8+ T-cell pool.51,52 The possibility that this quantitative difference reflects the use of tetramers able to detect CD8+ T cells restricted to selected human leukocyte antigen class I molecules cannot be excluded totally,53 but recent analysis performed using broad peptide libraries did not detect higher HCV-specific CD8+ T-cell frequencies.53,54 In addition, quantitative defects are not limited to the cellular arm of the adaptive response because antibody production of limited quantity and restricted to the immunoglobulin G1 isotype has been reported in acute HCV infections.37 Several factors likely are responsible for these defects of the adaptive immunity, including intrahepatic recruitment and subsequent deletion of activated virus-specific CD8+ T cells,55 antigen-driven T- or B-cell exhaustion,56 the ability of liver sinusoidal endothelial cells to suppress the expansion of T-helper 1-type cells,57 and the production of viral proteins with immunomodulatory effects.58-60 In addition, late appearance, reduced size, and functional T-cell defects detected in both primary HBV and HCV infections also might be a consequence of the inability of the innate immune response to provide an efficient containment of early virus replication and to promote timely and appropriate T-cell priming. Do available data allow support of this concept?
The innate immune response in HCV and HBV infections
One of the first defense mechanisms that an infected host is able to mount against viral infections is the production of type I IFNs. In addition to antiviral functions, these cytokines possess important immunomodulatory effects.61 The contribution and importance of type I IFNs have been deduced primarily from mouse models of different viral infections (lymphocytic choriomeningitis virus and murine cytomegalovirus).61,62 However, mice cannot be infected by HBV or HCV, and indications about the role of type I IFNs derive exclusively from recent studies in the chimpanzee model of HCV infection. Changes in the transcription of IFN- response genes have been shown to occur as early as 2 days after HCV infection in the liver of a chimpanzee acutely infected with HCV and these changes parallel the viral replication kinetics.63,64 HCV starts to replicate immediately after infection and viremia generally is detectable 1 to 2 weeks after inoculation in humans10 and within a few days in chimpanzees (Fig. 1).38,41,44 It is likely that HCV replication is the direct cause of type I IFN production because double-stranded RNA is a strong IFN- inducer.65 Although HCV is sensitive in vitro to IFNs,66,67 recent data raise the hypothesis that the virus may have developed strategies to interfere with the IFN type I antiviral activity.68 For example, the HCV E2 protein can inhibit in vitro the kinase activity of double-stranded RNA-activated protein kinase, one of the antiviral proteins induced by IFNs.69 Because of this interference, the initial production of type I IFNs only may be able to slow, but not block, virus replication. HCV viral kinetics are in line with this possibility. The initial rapid and early peak of viral replication can be followed by a period of about 4 to 6 weeks when HCV RNA can increase slowly or remain at stable levels10,38,41,44,63,64 in the absence of virus-specific T- and B-cell induction and liver inflammation.
The coexistence of HCV replication with the absence of signs of liver inflammation is not only indicative of the noncytopathic nature of HCV, but also calls into question the pathogenic contribution of natural killer (NK) and NK-T cells in HCV infection. NK and NK-T cells are components of the innate immune system that respond within minutes or hours after infection by producing IFN- and by killing infected cells.70 Although NK-T cells are a resident cellular population of the liver (high frequency of around 20% in mice and around 1% in humans),70 the majority of NK cells need to be recruited actively from the spleen.70 IFN- production by these cells not only has antiviral effects but also mediates the intrahepatic recruitment of inflammatory cells.71,72 Direct evidence of the activation state of NK and NK-T cells during the initial phase of HCV infection is lacking. Nevertheless, the absence of signs of liver inflammation in the first 4 to 6 weeks after HCV infection10,38,41,44,63 suggests that the contribution of NK and/or NK-T cells in this early phase may be minimal. This possibility also is supported by recent data showing that the HCV envelope protein E2 can inhibit natural killer cell functions directly73,74 by interacting with CD81, a tetraspannin molecule expressed on the surface of different cell lineages that is a putative HCV receptor.75 The direct inhibitory effect of the HCV envelope protein on global NK cell function may contribute to the absence of liver inflammation, despite the early signs of HCV replication and the early production of IFN-, which has been shown to promote NK cell recruitment into the liver.76 In line with this possibility, results obtained with DNA micro-array analysis of the chimpanzee liver63 show that the expression levels of IFN regulatory factor-1, a transcription factor essential for NK cell activity in vivo,77 does not change during acute HCV infection.
Is the pattern of innate immune response activation similar in HBV infection? As we have discussed previously, available data show a different replicative pattern after HBV and HCV infections . After an apparent initial quiescent phase of about 4 to 7 weeks,28,36,45,46 HBV starts to replicate vigorously, reaching levels of around 109 to 1010 copies/mL in 1 to 2 weeks,27,78 and infecting most hepatocytes.28,79-81 In animal models of HBV infection, this rapid peak of viral replication is accompanied in self-limited infection by a typical acute phase of disease with IFN- and TNF- production, followed by the triggering of the adaptive immunity.28,81 Animals that develop chronicity lack the acute phase response and fail to prime an adequate adaptive response.26,82,83 Thus, activation of innate components of the immune system seems to represent a key element in the control of the initial HBV burst. Available data do not allow the contribution of the individual components of the innate immunity to be dissected out. However, their overall efficiency is remarkable because the HBV-DNA quantity decreases by more than 80% within 2 to 3 weeks after the peak of viral replication,79,80 and before the peak of the antigen-specific CD8 response and liver damage.27,28,81
Is this initial IFN- production primarily sustained by NK and NK-T cells? Although we lack direct evidence of the role of NK and NK-T cells during natural HBV infection, a number of recent reports in animal models may be consistent with this hypothesis. NK-T cells in the transgenic mouse model of HBV infection have been shown to inhibit virus replication through the production of IFN-.72,84 In this system, the activation of NK-T cells was a consequence of -galactoceramide stimulation rather than a response to the natural infection. Nevertheless, recent results indicate that a population of nonclassic NK-T cells can be activated directly when injected into mice expressing HBV antigens in the liver.85 Thus, NK-T cells potentially could be triggered during natural HBV infection, by direct recognition of viral antigens, or, possibly, by the expression of stress signals either by infected hepatocytes or by liver dendritic cells. Strong evidence that NK and NK-T cells actually contribute to the initial control of HBV replication derives from work in acutely infected chimps. A rapid drop in viral replication occurs in the presence of intrahepatic IFN- production, before the massive intrahepatic recruitment of T cells. In this setting, NK or resident NK-T cells seem to be the principal source of IFN- production causing rapid inhibition of HBV replication and recruitment of virus-specific and nonspecific cells.72,86 A similar sequence of events has been reported in patients studied during the incubation phase of hepatitis B. An increased number of circulating NK cells precedes the peak of HBV replication, and is followed, 2 to 4 weeks later, by the appearance of HBV-specific CD8+ T cells, when viral replication has already dropped.27
Role of the dendritic cells in virus control
Dendritic cells (DCs) act as a link between innate and adaptive immunity. Signals delivered by the innate immune system (type I IFN production, interactions with NK cells) lead to the proper maturation of DCs, which are critical for triggering the antigen-specific immune response.87 The ability of DCs to induce T-cell responses also is influenced by their tissue localization, the antigen dose, and the interaction with helper T cells.87 Activation of cytotoxic T cells in lymph nodes draining the site of infection occurs hours after the initial challenge88 and is mediated by DCs. CD8+ T cells (but also CD4+ T cells) stimulated for only 24 hours by mature DCs proliferate extensively.89
Given the crucial role played by DCs in T-cell priming, we raise the hypothesis that an alteration of the DC function and/or maturation during primary HCV infection can contribute to the delayed appearance of HCV-specific CD8+ and CD4+ T cells after infection. Although no conclusive data are available about the function of DCs during acute or chronic HCV infection, it has been shown in vitro that the E2 protein of HCV can inhibit NK cell function directly.73,74 Because NK cell activation contributes to DC maturation,90 it is possible to speculate that this inhibitory effect may influence indirectly the function of DCs to trigger the adaptive response. Furthermore, experiments performed with monocyte-derived DCs indicate that these cells show an altered maturation process in chronic HCV infection,91-93 which may be related to the presence of HCV93 or to the effect of HCV proteins.94 Thus, it is possible, even though not directly proven, that the ability of DCs to pick up HCV antigens, to migrate to draining lymph nodes, or to induce proper T-cell activation is influenced by the high HCV levels present also during the early phase of HCV infection.
The situation seems to be different in primary HBV infection. Infection of DCs by HBV is even more controversial than in HCV, and the described functional defects are minimal.95-97 The delayed appearance of HBV-specific immune responses after primary infection seems to depend more on the kinetics of HBV replication (i.e., HBV persists for at least 5-8 weeks in the newly infected host without detectable signs of efficient replication), than on immune dysfunctions. The evidence that HBV-specific CD4+ and CD8+ T cells become detectable a short time after the exponential increase in HBV replication27,28 suggests that the DC function is not affected by the virus at the early phases of self-limited HBV infection.
The collapse of the adaptive immunity
When resolution of HBV and HCV infections is achieved, virus-specific antibodies as well as multispecific and T-helper 1-oriented CD4- and CD8-mediated T-cell responses remain detectable for several years.5,98,99 In contrast, the inability to control the infection and the establishment of chronicity lead to a progressive decline of the adaptive immunity with a lower number of circulating and intrahepatic virus-specific CD8+ and CD4+ T cells,100-103 as well as low and restricted production of virus-specific antibodies.37 Patients who develop chronic HCV infection show persistently defective CD8+ T-cell function,48-50 which probably is maintained by the combined effect of different mechanisms, including prolonged exposure of T cells to viral antigens,104 immunosuppression by viral gene products,58,59 and impaired DC accessory function.91-93 In chronic HBV patients, persistently high production of viral antigens can delete or tolerize antigen-specific T105 and B56 cells. HBV typically is able to produce large quantities of noninfectious subviral particles containing only envelope antigens and a secretory form of the nucleocapsid protein, called hepatitis B e antigen, that induces in transgenic mice the preferential production of T-helper 2 cytokines by deletion of T-helper 1 cells.106,107 Chronic exposure to HBV antigens has been shown to delete HBV-specific B cells56 and to cause an alteration of the hierarchy and function of HBV-specific CD8+ T cells, with a repertoire skewed toward subdominant epitopes. CD8+ T cells escaping deletion caused by large quantities of persisting antigen are characterized by an inability to bind specific human leukocyte antigen tetramers, and can be detected by intracellular cytokine staining.105 This CD8+ T-cell phenotypic alteration is not associated with a lower T-cell receptor affinity but potentially can reflect an altered T-cell receptor organization that can affect human leukocyte antigen-tetramer binding efficiency.108 The in vivo function of these tetramer/negative antigen-specific CD8+ T cells is unknown, but the inability to exert selective pressure on the infecting virus may suggest that they are anergic in vivo.105
The progressive qualitative and quantitative collapse of the adaptive immunity in both chronically HBV- and HCV-infected patients has a profound effect on the composition of the virus populations infecting individual patients. Because chronic patients are unable to control the infection rapidly, progressive selection of T- and B-cell escape variant viruses can occur. HBV and HCV variants carrying mutations in helper,109,110 cytotoxic,111-113 and B-cell114-117 epitopes have been detected in chronic hepatitis B and C and this selection is postulated to take place principally during the initial phases of infections.113,116,118 In HCV-infected chimpanzees, viral mutants that are able to escape CD8+ T-cell responses emerge early after infection.119-121 Furthermore, a longitudinal study of patients with chronic hepatitis C revealed that the sequences of CD8+ T-cell epitopes of the infecting viral populations did not diversify during several years of follow-up, despite the relatively high frequency of escape mutations initially present.118 Also, the selective pressure exerted by the humoral response acts early because mutations in B-cell epitope regions found in chronic HCV patients have been shown to develop in the initial phases of infection.116 At later stages, T- and B-cell epitopes appear to be fixed within the viral populations. This is a further indication of the progressive collapse of the immune response in persistent HCV and HBV infections resulting in the inability of the residual T- and B-cell activity to exert selective pressure on the virus.
FINAL REMARKS
Clarification of the virologic and immunologic events occurring during HBV and HCV infections not only allows us to better define the different mechanisms potentially involved in viral persistence, but also to understand why preventive HBV and HCV vaccines differ in the protection they provide against infection. Although the profile of the adaptive immune response against HBV and HCV infections is similar, the antiviral immune response can provide protection against HBV122 but not against HCV reinfection.123,124 Moreover, although a vaccine based on the envelope protein of HBV, which induces envelope-specific antibody122 and helper T-cell responses,125-127 can elicit a sterilizing anti-HBV immunity, different HCV vaccine preparations able to prime similar profiles of T- and B-cell responses have so far failed to protect animals from HCV infection.128,129 The different kinetics of HCV and HBV replication may represent one of the factors responsible for these differences. If HCV can survive the neutralizing effect of anti-HCV envelope antibodies32,130 that persist at low levels after natural HCV infection37 or immunization,129 a reservoir of replicating virus can be established immediately that may outpace the development of recall HCV-specific antibody and T-cell responses. It is interesting to note that HCV-specific cellular immune responses are detectable earlier after rechallenge (2 weeks) than after primary infection (8-10 weeks).39,41,128,131 This acceleration of the adaptive immune response, although insufficient to prevent infection, can influence positively the course of the HCV-induced liver disease in vaccinated animals, which usually develop low viremia and mild hepatitis. These findings in HCV rechallenge experiments and in HCV-vaccinated animals reinforce the hypothesis that the long interval of time between infection and activation of the HCV-specific adaptive immune response represents a major factor that influences the rate of chronicity and the profile of the disease. In contrast to HCV, HBV is controlled more easily by vaccination122 because its replication kinetics allows sufficient time for adaptive T- and B-cell responses to develop. This may explain why vaccination with HBV envelope antigens can prevent liver disease even if administered after HBV infection.132
In both infections, once chronicity develops, the common outcome is a progressive collapse of the immune system, which makes it unlikely that the host can spontaneously reacquire the capacity to control virus replication. At present, the treatment of chronic HBV and HCV infections relies on the use of drugs with direct antiviral effects. However, the different vigor and quality of the virus-specific immunity in self-limited versus chronic hepatitis suggests that therapeutic restoration of the antiviral immunity could lead to the control of virus replication and disease in chronically infected subjects. The real problem with the therapeutic vaccine approach is that the immune system of chronically HBV- and HCV-infected patients does not have the same functional efficiency and cell repertoire of subjects who have been able to control the infection. Therefore, strategies to optimize the efficacy of therapeutic vaccination are needed. In this perspective, efforts should be directed to develop vaccines not only designed to prime efficiently naive T and B cells89 but also to boost the antiviral efficiency of T cells co-existing with high antigen concentrations. For this purpose, inhibition of viral replication by antiviral drugs may be a strategy to restore the antiviral efficiency of the immune system. This is suggested by the observation that lamivudine treatment of chronically infected HBV patients can increase the frequency and improve the function of circulating HBV-specific helper and cytotoxic T cells.133,134 Data supporting the rationale of this approach recently have been reported in animal models of HBV infection, in which the efficacy of therapeutic vaccination is enhanced by previous antiviral treatment.135,136
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