Multiple inhibitory receptors may play a role in the weak or absent CD81 T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. In the present study, we investigated the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chronically infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was analyzed in virus-specific CD81 T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus (EBV), or influenza virus (Flu). In chronic HBV infection, virusspecific CD81 T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-specific CD81 Tcells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-specific proliferation and cytotoxicity as measured by the expression of CD107a, interferon-c, and tumor necrosis factor-a in CD81 T-cells. Conclusion: CD244 and PD-1 are highly coexpressed on virus-specific CD81 T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. CD244 may thus be another potential target for immunotherapy in chronic viral infections.
Chronic hepatitis C is characterized by a weak or absent hepatitis C virus (HCV)-specific CD4 ؉ T-cell response in terms of antigen-specific proliferation or interferon gamma (IFN-␥) secretion. To clarify whether this is due to the absence or functional impairment of antigen-specific CD4 ؉ T cells we developed an assay that relies on the induced expression of the T-cell activation marker CD25 and is therefore independent from cytokine secretion or proliferation. In 10 of 20 patients with chronic hepatitis C, a significant number of antigenspecific activated CD4 ؉ T cells (mean 1.06%/patient; range, 0% to 5.2% of CD4 ؉ T cells) could be shown, whereas antigen-specific proliferation was present in only 1 of 20 patients. IFN-␥ secretion was absent in all 13 patients tested. However, significant antigen-specific interleukin 10 (IL-10) and transforming growth factor  (TGF-) secretion was present in 6 of 10 and 3 of 10 patients, respectively. In 8 patients with acute hepatitis C, irrespective of disease outcome, HCV-specific CD4 ؉ T cells were detected in all patients and at a significantly higher frequency (mean 3.7%/patient; range, 1.16% to 7.17%) in the first weeks of disease. A chronic course of disease was associated either with a loss of both IFN-␥ secretion and proliferation, resembling an anergic state, or a loss of T-cell proliferation followed by a rapid decline in IFN-␥-producing cells, corresponding to exhaustion of the specific immune response. In conclusion, functional changes of HCV-specific CD4 ؉ T cells or failure to develop a long-lasting T-helper response may contribute to chronic hepatitis C viral persistence. ( C hronic hepatitis C affects 170 million individuals worldwide and is a major cause of liver cirrhosis and hepatocellular carcinoma. 1,2 Currently available antiviral therapies induce a sustained virologic response in only about 50% of treatable patients and are associated with considerable side effects and costs. 3 The fact that some patients with acute hepatitis C are able to spontaneously resolve hepatitis C virus (HCV) infection has fostered hopes that an immunotherapy, which induces an efficient antiviral immune response, could become a successful treatment of chronic hepatitis C. A prerequisite, however, for the development of an efficient immunotherapy is the characterization of the immune response that is associated with viral clearance. Of similar importance is a detailed understanding of the pathogenesis of chronic hepatitis C because certain mechanisms that facilitate viral persistence also could be amenable to therapy. In acute hepatitis C it has been shown by several groups that a strong and maintained HCV-specific CD4 ϩ T-cell response is associated with viral clearance 4-6 ; little is known, however, about the mechanisms that prevent the development or maintenance of an efficient antiviral immune response in patients developing chronic hepatitis C. A better understanding of the detailed kinetics and function of HCV-specific CD4 ϩ T cells requires new immunologic techniques ...
The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.Hepatitis C virus (HCV) acts as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. To date, HCV infection is one of the primary causes of liver transplantation in the United States and other countries. More than 170 million individuals have been reported to be seropositive worldwide (40). There is no sufficient prophylaxis by vaccination, and antiviral therapy with a combination of alpha interferon (IFN-␣) and ribavirin is effective only in selected patients. This underlines an urgent need to improve our knowledge of virus-cell interactions and immune escape mechanisms. Elucidation of the mechanisms by which HCV interacts with and regulates the immune response, especially in the early stages of infection, is likely to lead to productive insights into how to combat chronic infection and prevent its serious complications.HCV has been classified as the sole member of a distinct genus called Hepacivirus in the family Flaviviridae. The characteristic all of these viruses have in common is a positivestranded RNA that, in the case of HCV, consists of a genome of approximately 10 kb containing one large open reading frame (ORF) that is initially translated into one single polyprotein and subsequently cleaved into the functional proteins. The putative organization of the HCV genome includes the 5Ј-untranslated region, four structural proteins, six nonstructural proteins, and a 3Ј-untranslated region (41). Among the structural proteins of HCV, the basic 19-kDa core protein exhibits pleiotropic features. It may be involved in nucleocapsid formation, and it plays a role in the switch between viral polyprotein synthesis and subsequent viral RNA replication. In addition, HCV core protein was shown to transcriptionally regulate several cellular and viral genes (28). Furthermore, severalalthough in part contradictory-reports suggest an influence of the HCV core protein on the transcriptional activity of p53 and the regulation of p53-dependent genes. Both suppression and upregulation of p53-dependen...
Chronic evolution of acute hepatitis C (aHC) occurs in more than 80% of patients but can frequently be prevented by early treatment with interferon (IFN)-␣. Plasmacytoid dendritic cells (pDCs) are the major endogenous IFN-␣ producers, but their role in aHC is unknown. In this study, frequency, phenotype, and pDC function were analyzed in 13 patients with aHC and 32 patients with chronic hepatitis C (cHC) compared with 20 healthy controls, 33 sustained responders to antiviral treatment, 14 patients with acute hepatitis B (aHB), and 21 patients with nonviral inflammatory disease. In aHC, pDCs in the peripheral blood were significantly reduced compared with healthy controls (median, 0.1% vs. 0.36%, P < .0005) and were inversely correlated to alanine aminotransferase levels (r ؍ ؊0.823; P < .005). Circulating pDCs in aHC were immature, as determined via reduced expression of HLA-DR and CCR7, and produced little amounts of IFN-␣ (median, 3.5 pg/50,000 peripheral blood mononuclear cells [PBMCs] vs. 498.4 pg/50,000 PBMCs in healthy controls; P < .0005). Less pronounced changes were present in cHC (median, 0.17%, 28.0 pg/50,000 PBMCs IFN-␣, respectively). However, a significantly reduced frequency and IFN-␣ production was also found in self-limited aHB (median 0.1%, 8.6 pg/50,000 PBMCs) and in patients with nonviral inflammatory disease (median 0.19%, 7.5 pg/50,000 PBMCs). In conclusion, in aHC frequency and IFN-␣-producing capacity of peripheral blood pDCs are dramatically reduced and inversely correlated with the degree of liver inflammation. In cHC there is incomplete recovery of pDC function, which, however, could be solely due to the chronic inflammatory state. (HEPATOLOGY 2005;41:643-651.) H epatitis C virus (HCV) infection leads to chronic viral persistence in the majority of newly infected patients. Nevertheless, approximately 15% of all patients and up to 50% of symptomatic subjects with acute hepatitis C (aHC) spontaneously achieve long-term viral clearance, 1 which is attributed to a strong HCV-specific CD4 ϩ T helper 1 and CD8 ϩ cytotoxic T-cell response. [2][3][4][5] In contrast, once chronic HCV persistence is established, spontaneous viral clearance becomes extremely rare. 6 The acute and chronic phases of HCV infection also differ remarkably in their response to antiviral treatment: whereas in chronic hepatitis C (cHC), a combination treatment of pegylated interferon (IFN)-␣ and ribavirin is required to achieve approximately 50% of sustained virological response, 7,8 in aHC, monotherapy with conventional IFN-␣ leads to more than 95% sustained viral clearance. 9 The reasons for the difference in treatment response between aHC and cHC are currently not understood. Nevertheless, it seems that the substitution of IFN-␣ in the early phase of virus-host interaction during aHC successfully interferes with a process that is required for chronic viral persistence, suggesting that type I IFNs play a central role in the initial interaction between HCV and the host.
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