Hepatitis C Virus Inhibits Cell Surface Expression of HLA-DR, Prevents Dendritic Cell Maturation, and Induces Interleukin-10 Production

Saito, Ko; Ait-Goughoulte, Malika; Truscott, Steven M.; Meyer, Keith; Blazevic, Azra; Abate, Getahun; Ray, Ratna B.; Hoft, Daniel F.; Ray, Ranjit

doi:10.1128/jvi.02547-07

Cited by 75 publications

(68 citation statements)

References 43 publications

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“…Our results suggested that IRF-1 expression was significantly reduced in NS5A-expressing cells but remains unaffected in core-expressing cells, indicating a more pronounced effect of NS5A on C4 regula-tion. This observation is in agreement with our previous reports that HCV core protein does not activate IRF-1 or class II transactivator (CIITA) promoter activity (3,28). We have also observed that the basal IRF-1 expression at the mRNA level was not altered in the presence or absence of IFN-␥ compared to control hepatocytes.…”

Section: Discussionsupporting

confidence: 93%

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Banerjee

Mazumdar

Meyer

et al. 2011

J Virol

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The fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-␥)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-␥-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.The complement system is a set of biochemical pathways that helps to clear pathogens from an organism as part of the innate and acquired immunity programs. Activation of the complement system triggers a wide range of cellular responses ranging from apoptosis to opsonization (27). The complement system plays a critical role in the pathogenesis of a variety of chronic human diseases. Viruses have been shown to attenuate complement activation. Recently, the nonstructural protein (NS1) from flaviviruses (dengue fever virus, West Nile virus, and yellow fever virus) has been reported to attenuate complement activation by interacting with several complement components (1,8). Results from another study suggest that the complement system is also involved in the pathogenesis of a variety of liver disorders, including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury (24). The fourth component of the complement system, C4, plays a vital role in mounting a proper immune response against infection (35). Chronic hepatitis C virus (HCV) infection is a leading cause of progressive liver disease. The mechanisms responsible for HCV persistence are not well understood, although the interactions between HCV and host cells appear to play an important role. Dumestre-Perard et al. (11) reported in a study of a large cohort that in patients with chronic HCV infections, the blood level of specific complement components is depleted, and C4 activity is significantly lower. A decrease in specific C4 activity was reported among relapsers compared with sustained responders, before and during therapy, suggesting it...

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Section: Discussionsupporting

confidence: 93%

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Banerjee

Mazumdar

Meyer

et al. 2011

J Virol

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“…Pervious studies have shown that increased arginase-1 or ROS generation could explain the mechanism of suppressive MDSCs in chronic virus infection (19)(20)(21). However, our study supports that upregulation of IL-10 represents the major mechanism for suppressive MDSCs in CHB patients, similar to previous reports for several other human diseases (27,38,39). These cells could spontaneously secrete bioactive IL-10 ex vivo, a feature undetectable in healthy control MDSCs.…”

Section: Discussionsupporting

confidence: 90%

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Huang

Zhang

Yan

et al. 2014

The Journal of Immunology

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Although myeloid-derived suppressor cells (MDSCs) are well known for their immunosuppressive function in several pathological conditions, the role of MDSCs in hepatitis B virus infection remains obscure. In this study, we investigated the frequency and function of MDSCs in the peripheral blood and liver of 91 chronic hepatitis B (CHB) patients. A higher percentage of MDSCs, defined as CD14+HLA-DR−/low, was detected in peripheral blood of CHB patients than that of the healthy controls. Moreover, high expression of programmed death 1 (PD-1) and secretion of IL-10 in this population were determined. The frequency of MDSCs was positively correlated with serum viral load, but it was negatively correlated with liver inflammatory injury. These cells were also abundant in liver tissue of CHB patients and were related to necroinflammatory activity. Furthermore, we found that these cells could suppress hepatitis B virus–specific CD8+ T cell response, including reduced proliferation and IFN-γ production, and inhibit degranulation of CD8+ T cells, including reduced production of granzyme B and perforin. Importantly, PD-1–induced IL-10 production by MDSCs was responsible for the suppressive activity. To our knowledge, for the first time our study proved that CD14+HLA-DR–/lowPD-1+ MDSCs in CHB patients contribute to an inadequate immune response against the virus and lead to chronic infection, which represents a potential target for therapeutic intervention.

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“…Indeed, the immune response against herpes simplex virus was suppressed by blocking the autophagy (6). With regard to HCV, functionally impaired DC dysfunctions marked by poor DC maturation, impaired antigen presentation, and attenuated cytokine production have been reported in tissue culture models and chronic hepatitis C patients (1,22,46). In addition, reduction of cell surface expression of MHC-I in HCV genotype 1b replicon cells has been reported (55).…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Taguwa¹,

Kambara²,

Fujita

et al. 2011

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and the elimination of invasive microorganisms. In addition, disruption of autophagy often leads to several protein deposition diseases. Although recent reports suggest that HCV exploits the autophagy pathway for viral propagation, the biological significance of the autophagy to the life cycle of HCV is still uncertain. Here, we show that replication of HCV RNA induces autophagy to inhibit cell death. Cells harboring an HCV replicon RNA of genotype 1b strain Con1 but not of genotype 2a strain JFH1 exhibited an incomplete acidification of the autolysosome due to a lysosomal defect, leading to the enhanced secretion of immature cathepsin B. The suppression of autophagy in the Con1 HCV replicon cells induced severe cytoplasmic vacuolation and cell death. These results suggest that HCV harnesses autophagy to circumvent the harmful vacuole formation and to maintain a persistent infection. These findings reveal a unique survival strategy of HCV and provide new insights into the genotype-specific pathogenicity of HCV.Hepatitis C virus (HCV) is a major causative agent of bloodborne hepatitis and currently infects at least 180 million people worldwide (58). The majority of individuals infected with HCV develop chronic hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma (25,48). In addition, HCV infection is known to induce extrahepatic diseases such as type 2 diabetes and malignant lymphoma (20). It is believed that the frequency of development of these diseases varies among viral genotypes (14, 51). However, the precise mechanism of the genotype-dependent outcome of HCV-related diseases has not yet been elucidated. Despite HCV's status as a major public health problem, the current therapy with pegylated interferon and ribavirin is effective in only around 50% of patients with genotype 1, which is the most common genotype worldwide, and no effective vaccines for HCV are available (35, 52). Although recently approved protease inhibitors for HCV exhibited a potent antiviral efficacy in patients with genotype 1 (36, 43), the emergence of drug-resistant mutants is a growing problem (16). Therefore, it is important to clarify the life cycle and pathogenesis of HCV for the development of more potent remedies for chronic hepatitis C.HCV belongs to the genus Hepacivirus of the family Flaviviridae and possesses a single positive-stranded RNA genome with a nucleotide length of 9.6 kb, which encodes a single polyprotein consisting of approximately 3,000 amino acids (40). The precursor polyprotein is processed by host...

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Hepatitis C Virus Inhibits Cell Surface Expression of HLA-DR, Prevents Dendritic Cell Maturation, and Induces Interleukin-10 Production

Abstract: Hepatitis C virus (HCV) chronic infection is

Cited by 75 publications

References 43 publications

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

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