Semmo N, Klenerman P. CD4+ T cell responses in hepatitis C virus infection. World J Gastroenterol 2007; 13(36): 4831-4838 [PMID: 17828814 DOI: 10.3748/wjg.v13.i36.4831]
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Paul Klenerman, Nuffield Department of Clinical Medicine, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom. firstname.lastname@example.org
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CD4+ T cell responses in hepatitis C virus infection
Nasser Semmo, Paul Klenerman
Nasser Semmo, Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany
Paul Klenerman, Nuffield Department of Clinical Medicine, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Supported by the Deutsche Forschungsgemeinschaft and the Wellcome Trust and the James Martin School for the 21st century, Oxford
Correspondence to: Paul Klenerman, Nuffield Department of Clinical Medicine, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom. email@example.com
Telephone: +44-186-5281885 Fax: +44-186-5281236
Received: June 26, 2007 Revised: July 2, 2007 Accepted: July 9, 2007 Published online: September 28, 2007
Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are relatively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type I profile, which promotes cellular effector mechanisms are thought to be more likely to experience viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells, especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in determining the outcome of acute and chronic HCV infection will be discussed in this review.
Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Since the discovery of the virus, considerable evidence has emerged that CD4+ T cell responses to HCV play a key role in the outcome of infection. However many questions remain and these will be discussed in this review.
Cellular immune responses, involving both CD8+ cytotoxic T lymphocytes (CTL) and CD4+ T-helper cells, play an essential role in the control of HCV infection, as they do in other persistent viral diseases. Whereas CTLs are traditionally thought to be the main effector cells that eliminate HCV-infected cells, it is clear that HCV-specific CD4+ T cells also play a critical role. These cells can potentially act in multiple ways and are central to the initiation and maintenance of adaptive immunity. Two likely major roles are in providing help for CD8+ T cells by cytokine production and activation of antigen-presenting cells, but there are multiple other mechanisms of action including direct antiviral effects, a role in B cell maturation, and regulatory functions.
A very clear example of the overall importance of HCV-specific CD4+ T cell responses in vivo is an experiment where the antibody-mediated depletion of CD4+ T cells before re-infection of two immune chimpanzees was performed. Such depletion resulted in persistent, low-level viraemia despite functional intra-hepatic memory CD8+ T cell responses. In this experiment incomplete control of HCV replication by memory CD8+ T cells in the absence of adequate CD4+ T cell help was associated with emergence of viral escape mutations in Class I MHC-restricted epitopes and failure to resolve HCV infection. This experiment is important in that it shows that CD4+ T cells are necessary for resolution of HCV infection. However, in this case the exact function of the CD4+ T cells was not elucidated. The fact that CD8+ T cell responses were maintained and were functional (inducing viral escape) suggests that their role is not purely in providing support for CD8+ T cell responses.
Overall, most data on CD4+ T cells comes from experiments in infected persons, particularly those comparing chronic and resolved infection. During chronic HCV infection, HCV-specific CD4+ T cell responses are typically described as weak or absent whereas in resolved infection these responses are generally vigorous and multispecific. However, much of the data is derived from cross sectional studies and also based on analysis of one function-proliferation in vitro. There is no doubt that CD4+ T cell responses in resolved infection and in persistent infection look very different, but how they diverge and what the true functionality of the populations are is not yet clear. In our view, given their central importance in adaptive immunity, understanding why CD4+ T cell responses may fail in acute infection is the key question in HCV pathogenesis. Current data on the function and role of virus-specific CD4+ T-helper cells in acute and chronic HCV infection will be reviewed here and models discussed.
CD4+ T CELL RESPONSES IN ACUTE HCV INFECTION
Clearly, the best place to study the CD4+ T cell response against HCV is at the site of infection, but CD4+ T cell responses in the liver of acute HCV infection in humans have not been characterized to date. In chimpanzees, liver CD4+ T cells have been expanded with anti-CD3 and IL-2 and then tested for proliferation in response to HCV proteins. In those who failed to control the virus, no CD4+ T cell responses were identified whereas in those chimps who transiently or permanently controlled the virus, strong proliferative CD4+ T cell responses were detectable. This experiment is limited by the need to expand the cells first in vitro, which might exclude certain cell populations, especially at the peak of infection. What is interesting is not only the dichotomy between those animals that cleared virus and those that did not, but also the “transient” group. This group does mount an early CD4+ response against HCV, but it is not sustained. The clinical phenomenon of transient control is common in human infection, with “yo-yo” patterns often described, and will be discussed further below.
All human studies in acute disease have been performed on blood. In these, overall, acute resolving HCV infection has been associated with a sustained response by HCV-specific CD4+ T cells. In one representative study patients who failed to clear the virus were divided into two groups. Group 1 was unable to mount an HCV-specific CD4+ T cell response and developed chronic HCV. In Group 2, HCV RNA was cleared initially and was associated with strong HCV-specific CD4+ T cell responses. However, these responses diminished just before a rebound of viraemia that resulted in chronic infection. Therefore, a vigorous anti-viral CD4+ T cell response (as measured by proliferation assays) in the early and late phase of acute HCV seems necessary to achieve long-term viral control (CD4+/Th1 response). However, it is not sufficient (as in the chimpanzees), since those who mount such a response do not necessarily go on to clear virus.
Although what the Gerlach paper described is especially clear cut in relation to the “yo-yo” pattern, other groups have also reported that the vigour of the T cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection. That persistent infection can develop despite the presence of acute-phase HCV-specific CD4+ T cell responses has been shown in a study of healthcare workers exposed to needle-stick injuries: although two individuals had strong HCV-specific CD4+ T cell proliferative responses in the acute phase with significant decreases in HCV RNA initially, they subsequently became chronically infected. This was an important study since the individuals were available for analysis shortly after infection-before clinical symptoms arose. Since responses are sometimes transient, it may be that in studies where patients are only analysed after they present clinically with acute infection, early T cell responses have been missed.
Such analyses have traditionally relied on proliferation. Using alternative techniques, it has been shown that evolution of the infection to chronicity can be associated with HCV-specific CD4+ T cells which survive initially despite failing to proliferate or produce IFN-γ: these diminish eventually as infection persists. A study of a single patient using a novel approach with Class II MHC peptide complexes (“tetramers”) revealed the loss of functionality of cells before the final loss of detection of such populations. The failure of such responses in this patient occurred before the re-emergence of virus after transient control. This is important since it suggests that not all the failure of CD4+ T cell responses may occur as a consequence of prolonged viremia.
Overall, these studies suggest that a range of HCV-specific CD4+ T cell responses in the acute HCV phase can exist in blood and liver. In a subgroup of individuals, it may be that CD4+ T cell responses are not mounted initially, or are not detectable at the time of presentation. These individuals are very likely to develop chronic infection. In another group, strong responses are detected and sustained, which is typically associated with resolution of infection. An important third group (probably the majority of patients) do mount a CD4+ T cell response initially, but loss of such responses is associated with progression to chronicity. What the differences are in these initial responses to HCV and why certain key CD4+ T cell responses are not sustained remain important questions in understanding HCV persistence. To understand this further it is necessary to consider the exact targets of the CD4+ T cell response.
TARGETS OF THE CD4+ T CELL RESPONSES IN HCV INFECTION
A more effective immune response against HCV could result from targeting more epitopes, mounting larger responses or targeting a key region. There is some evidence for all three. Overall, permanent resolution of infection has been related to both the breadth (number of CD4 epitopes targeted) and the magnitude of HCV-specific CD4+ T cell responses. While no one target has been identified as the key determinant, a number of candidates have been proposed.
The NS3 protein has been shown to be one dominant target of CD4+ T cell responses in humans clearing HCV infection. Some epitopes in NS3 have been identified in both humans and chimps with resolved infection (see below)[11-14]. Numerous studies indicate that CD4+ T cells targeting most HCV proteins, including non-structural (NS) proteins, are the norm in self-limited infections[3-6,10-11,15-17]. However, some caution is needed in interpreting the exact targeting as the genomic variation between different HCV genotypes is substantial and relatively non-conserved epitopes (as might occur in envelope genes) may not always be picked up in such screens.
The number of CD4+ T cell epitopes recognised during acute HCV infection has been estimated by characterising memory CD4+ T cell populations in blood after permanent resolution of the virus: one study showed at least four, and up to 14 epitopes from the core, NS3, NS4 and NS5 proteins were recognised by CD4+ T cells in patients several months or even years after loss of HCV RNA. A recent study identified 13 CD4+ T cell epitopes within the NS3-NS4 region that were recognised by ≥ 30% of patients with acute or resolved HCV. Of these, eight peptides were also recognised recurrently from different donors by specific CD4+ T cell clones in independent cloning procedures. Multispecific CD4+ T cell responses were also detectable in blood of individuals during acute HCV infection acquired by needlestick injury or IV drug use. Importantly, in some patients whose infection became chronic after the acute phase infection, responses were similar to those who spontaneously cleared the virus after acute infection. The only difference (as above) was that these responses in individuals with chronic infection were not sustained.
A recent study identified a single epitope restricted by HLA DR1 (a common HLA molecule) in NS4, which appears to be very commonly targeted in infected individuals (Table 1). New analysis using Class II tetramers revealed that in acute infection, all DR1+ donors made a response to this peptide. This highly reproducible response is somewhat unusual, but may reflect the fact that this peptide is extremely conserved. Although the responses at presentation were indistinguishable between those who went on to resolve infection or not, early loss of tetramer+ cells was seen in those with persistent infection. The loss of such cells was not associated with mutation within the epitope and populations of such cells were not found localised in the liver only. Interestingly, when compared to controls in long term chronic infection, some very low level tetramer+ populations could be identified in the absence of proliferative responses. This suggests that specific responses were not deleted entirely, but persist at very low levels and with only limited function.
Table 1 Displays the most commonly described CD4+ restricted epitopes.
Amino acid position
Amino acid sequence
DRB1*15, DRB1*0301 +
DRB1*1101,DRB1*1201, DRB1*0401, DRB1*1302
DRB1*16 or DRB3*0202
Table 1 HCV T helper epitopes mapped within a region of 21 amino acids or less. The protein, the sequence and HLA restriction elements of the T helper epitopes are provided.
ASSOCIATION BETWEEN HLA CLASS II ALLELES AND INFECTION OUTCOME
It is not yet clear whether responses to specific epitopes are clearly related to outcome. However, the T cell response to peptides derived from the virus is directed by the MHC genotype, and this could have a major influence on the quality of T cell responses. Importantly, some MHC Class II alleles in humans have been associated with persistence or resolution of HCV infection. For example, HLA-DRB1*0701 has been shown to be associated with persistence in patients who were homogeneous in terms of gender, source of infection (genotype 1b) and ethnicity. In contrast, a number of other studies of more mixed populations have shown a strong association between other HLA Class II alleles and viral control. These alleles are HLA-DRB1*0101, HLA-DRB1*1101, and HLA-DQB1*0301[21-23].
Although specific HLA alleles have been defined as protective, the link between the possession of a specific allele and the presentation of a specific peptide or set of peptides has not yet been made. HLA-DRB1*1101 and HLA-DQB1*0301 (these genes are in close linkage disequilibrium) have been associated with a sustained CD4+ T cell response in resolved HCV infection; these responses were stronger than in non-DQB1*0301+ controls. However, our understanding of this association still remains incomplete. Some of these HLA Class II restricted peptides have been identified through epitope prediction programs, and the full repertoire of naturally presented peptides is not completely defined. A recent study showed that viral variation might play a role in determining the dominance of epitopes seen within a population. Here, an HLA DR11-restricted epitope (NS3 aa1248-1261) that is highly conserved within viral genotypes was found not to be the immunodominant response, despite being the most commonly recognised epitope for this HLA allele. Epitopes in viral regions that can tolerate amino acid substitutions may thus appear to be less dominant, even if they are important. This is because their capacity for increased variability means that they may not occur in the prototype viral peptide sequences often used for immunological study, or might only be represented in a fraction of the patients studied.
CD4+ T CELL QUALITY AND ASSOCIATION WITH ACUTE OUTCOME
It has been suggested in studies of acute disease that viral clearance is more likely to occur when HCV specific responses of patients display a Th1 profile (IFN-γ and IL-2). Those with a more typical Th2 profile (IL-4 and IL-10) were more likely to become chronic suggesting that the Th1 phenotype generates more protective immune responses in HCV. In that study, CD4+ T-cell proliferation and cytokine secretion in response to a panel of recombinant HCV antigens were assayed in 17 patients with acute HCV. All six patients with self-limited disease had a significant CD4+ T-cell proliferation to C22, E1, C100, C200, and NS5, running parallel with the antigen-stimulated secretion of IL-2 and IFN-γ, but not with IL-4 and IL-10, indicating predominant Th1 responses. Among the remaining 11 patients who developed chronicity, several cases showed specific CD4+ T cell responses, but their antigen-stimulated IL-2 and IFN-γ production were significantly lower than those of cases with recovery. Importantly, IL-4 and IL-10 (Th2 responses) were detectable in the group who developed chronicity. The data suggested that activation of Th2 responses in acute hepatitis C patients might play a role in the development of chronicity, but much more work needs to be done in this area, and why such responses might differ at the start of the disease needs some explanation.
HCV SPECIFIC RESPONSES IN CHRONIC INFECTION
As discussed above, once chronic HCV infection is established, cellular immune responses are rarely or barely detectable using current technology. Several groups have aimed to analyse these HCV-specific CD4+ T cell responses during chronic HCV infection using proliferation assays, cytokine assays and, more recently Class II tetramers.
Analysis of HCV-specific CD4+ T cell responses in chronic HCV infection using ELISpot or ICS showed responses at low frequency in blood and only targeted a limited number of epitopes[4,7,11,15-17,28]. In an expanded analysis of responses to recombinant HCV proteins in persons with resolved infection, an average of 10 epitopes was targeted, whereas in persons with chronic viraemia never more than one epitope was targeted.
The question of whether HCV-specific CD4+ T cell responses persist in chronic infection but lack function in terms of proliferation and cytokine production (IFN-γ) has been addressed by staining for expression of the IL-2 receptor α-chain (CD25), which is an early marker of activation in a study that showed that a small proportion of CD4+ T cells from the blood of chronically infected individuals did upregulate CD25 after stimulation with recombinant HCV proteins, but lacked the capability for proliferation and IFN-γ production. However, the use of the marker CD25, which is present normally on a fraction of CD4+ T cells including Tregs, limits the usefulness of this assay.
It has generally been assumed that loss of proliferation equates to loss of the specific T cell populations. Low levels of IL-2 secretion have been shown in independent studies in humans and mice to be accompanied by a loss of proliferative capacity both in vitro and in vivo[29-32]. In HCV infection, recent data suggest that, in the presence of viraemia, HCV-specific CD4+ T cell populations do exist but lack proliferative capacity. This status is associated with the production of IFN-γ upon antigen stimulation, but little or no IL-2 is expressed (Figure 1).
Figure 1 Cytokine secretion patterns in persistent versus resolved HCV infection.
The best approach for detecting functionally impaired CD4+ T cells in chronic HCV infection is the use of MHC Class II tetramers. Using this technique, a correlation has been shown between the clinical outcome and the presence of circulating CD4+ T cells directed against the virus. Here, with the use of 3 HCV HLA Class II tetramers, HCV-specific CD4+ T cells could be detected in subjects who spontaneously resolved HCV viraemia, but not in those with chronic HCV infection, suggesting that HCV-specific CD4+ T cell frequencies are very low in PBMC. A further application of this technology for the analysis of intrahepatic CD4+ T cells could shed important light on their differentiation state and functionality.
The expansion of HCV-specific CD4+ T cell lines by repeated stimulation with recombinant antigens indicated that antigen-specific populations do persist[36-38]. A note of caution should be injected here in the analysis of sustained CD4+ T cell responses in chronically infected patients. In many cases, these may represent a historical response to a previous viral genotype which is no longer circulating in the patient. In one case described, the response was directed against genotype 1 even though the patient carried genotype 3, with a historical genotype 1 infection. Since the peptide in the genotype 3 sequence was substantially different and not recognised by host CD4+ T cells, this indicates that the detected response is effectively a memory response after removal of the original virus. Since super-infection is relatively common, this issue may be a substantial one for both CD4+ and CD8+ T cells.
The role of IL-10 as Th2 anti-inflammatory cytokine has been demonstrated in vivo in humans chronically infected with HCV. Here, individuals with advanced fibrosis were treated three times a week with IL-10 for 12 mo. Administration of IL-10 resulted in a decreased number of IFN-γ-secreting HCV-specific CD4+ and CD8+ T cells. At the same time ALT levels as a marker of inflammation were reduced, indicating the role of IL-10 as anti-inflammatory cytokine. However, with the loss of specific CD4+ and CD8+ T cells, HCV RNA levels were increased, suggesting that these same cells are responsible for viral control.
One hypothesis why in chronic HCV the Th2 type may occur is that dendritic cells from patients with chronic HCV infection have defective function, possibly due to inhibition of IL-12[42,43]. The latter cytokine is required for the induction of Th1 type cells. This dendritic cell dysfunction might result in biased T cell polarisation which could favor, for example, a Th2-type response. However, to what extent this is a major factor in pathogenesis is still controversial and the findings are not uniformly reproducible.
Overall, failure of CD4+ T cells is a key factor in HCV persistence and clearly in chronic disease there are relatively few functional CD4+ T cells to find, by whatever method. To some extent this appears to be due to loss/deletion of antigen-specific cells. On the other hand there is some evidence that a change in function also occurs in persistent infection, although whether this is cause or effect requires a great deal more study. It should be noted that although CD4+ T cell responses are regarded as weak in chronic HCV mono-infection, they are even weaker in HCV/HIV co-infection[44,45]. Since co-infection is associated with an increase of HCV load of about 0.5-1 log, this data suggests that in chronic mono-infection the remaining CD4+ T cell response is still playing a significant role.
MODELS FOR FAILURE OF CD4+ T CELL RESPONSES
If failure of the CD4+ T cell response against HCV is associated with virus persistence, what mechanisms could account for this? Here we outline three major contenders, escape, exhaustion and regulation.
Escape through mutation
Numerous studies in both animal and human models have documented immune escape from virus-specific CTL responses by viral mutations in CTL epitopes that lead to loss of immune control and viral persistence[46-52]. Less information is currently available about the potential for immune escape from viral CD4+ T cell epitopes, although limited studies in chronic HIV and HCV infection have identified multiple autologous virus variants for specific CD4+ T cell epitopes[53-56]. Peptides corresponding to viral variants were synthesised and tested in in vitro assays, and the majority of variants failed to stimulate proliferation or cytokine production by CD4+ T cells[54-56]. That viral variants may play a role in HCV persistence has also been shown previously in a study with four HLA-DRB1*15 patients chronically infected with HCV. Here, naturally occurring single amino acid substitutions in the DRB1*15-restricted Th1 epitope (aa 358-375) in the NS3 protein failed to stimulate proliferation. This was also accompanied by a shift in cytokine secretion patterns from one characteristic of a Th1 anti-viral response to a Th2 form. These data suggest that viral immune escape from specific CD4+ T cell responses is possible, but clear data showing the evolution of CD4+ T cell escape mutants in response to T cell selection pressure are still needed.
A recent study analyzed the effects of an induced T-cell response in three immunized chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. The immunized animals were challenged with clonal HCV, which had the same sequence as the antigens used for immunization. Persistent control of the virus was observed in two animals, whereas in the third animal viral control was transient, followed by a resurgence concomitant with the emergence of new dominant viral populations bearing single amino acid changes in the NS3 and NS5A regions. These mutations resulted in a loss of CD4 T-cell recognition and subsequent to viral resurgence and immune escape a large fraction of NS3-specific T cells became impaired in their ability to secrete IFN-γ and proliferate.
In addition to escape from virus-specific T cell responses, escape from neutralising antibody (nAb) responses is thought to be one potential mechanism leading to the persistence of some viruses with knock on effects on CD4+ T cells[53,59,60]. Recent data generated in an LCMV model have provided additional insight into the relationship between CD4+ T cells and immune escape from nAb responses. CD8-/- mice were infected with the WE strain of LCMV to establish a long-term infection with high levels of virus production that is transiently controlled by nAbs. However, the lack of CD8+ CTL responses and consequently high viraemia in this model leads to escape from polyclonal nAb responses. Associated with this is the rapid induction of CD4+ T cell unresponsiveness. Although the molecular mechanism of CD4+ T cell unresponsiveness is not clear from this study, it has been postulated that the high antigenic load in this model system may have resulted in activation of all virus-specific CD4+ T cells, leading to exhaustion and activation-induced cell death as has been described for CTLs[62,63]. Importantly, in the absence of LCMV-specific CD4+ T cells, these mice failed to generate new effective humoral responses against emerging neutralisation-escape mutants and the viral infection persisted. These data provide further evidence for the importance of interactions between the cellular and humoral immune responses for efficient control of viral infections. A similar phenomenon of exhaustion of CD4+ T cells could easily arise through any mechanism, which leads to long-term viremia, including escape from interferon or mutation in epitopes recognised by CD8+ T cells.
Recent years have seen a revival of interest in the role of regulatory T cells-notably the CD4+ CD25+ FoxP3+ subset. It is plausible that in HCV infection excessive regulation is involved in the suppression of HCV specific T-cell responses. Recently, CD4+ CD25+ regulatory T-cell activity has been shown to be present in patients with chronic HCV infection, which may contribute to weak HCV-specific T-cell responses and viral persistence[65-69]. An important question that derives from these studies is to what extent the Treg activity seen in persistent infection relates to the activity of antigen-specific cells. Treg cells may arise in the thymus (natural Tregs) but additionally virus-specific cells, which are repetitively stimulated with antigen over time, may develop regulatory characteristics. This activity may be promoted by the action of dendritic cell subsets modulated by persistent viremia. Such Treg cells might serve to downregulate both CD4+ and CD8+ T cell responses in persistent infection, particularly within the inflamed liver. A recent study revealed that approximately one in two to one in three CD4+ T cells in the liver of chronically infected patients are FoxP3+, a remarkably dominant potential Treg population. This could have a major effect on the maintenance and growth of antigen-specific CD4+ and CD8+ T cells.
HCV specific CD4+ T cells hold a pivotal role in disease pathogenesis. There is a consensus that there are real differences between the responses seen in resolved infection vs persistent infection, although to what extent these are cause or consequence is not clear yet. The differences include not only number, but also function, including cytokine secretion, such as the key mediator IL-2. A number of pieces of evidence point to the fact that a robust CD4+ T cell response is associated with a good outcome from acute infection and there is no doubt that such responses should be elicited in a vaccine. To what extent it matters which epitopes are targeted or not is not yet clear, but most observers argue that breadth is important, especially given the huge genomic variation in HCV, and that numbers are important. For those lucky enough to inherit protective HLA types, a vaccine may simply augment an already favourable response and sustain adaptive responses from CD8+ and B cells. For the rest, perhaps a pool of CD4+ T cell responses which are primed in a normal uninfected individual, and which can expand rapidly during acute infection may be sufficient to tip the balance in favour of host clearance.
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