scholarly journals Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus

2004 ◽  
Vol 78 (12) ◽  
pp. 6151-6161 ◽  
Author(s):  
Marie Larsson ◽  
Ethan Babcock ◽  
Arash Grakoui ◽  
Naglaa Shoukry ◽  
Georg Lauer ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonhuman Primates ◽  
Cd40 Ligand ◽  
Good Manufacturing Practice ◽  
Hcv Infection ◽  
Migration Capacity ◽  
Chronic Hcv

ABSTRACT Dendritic cells (DCs), which are potent antigen-presenting cells (APCs), are used as adjuvants for the treatment of cancer and infectious diseases in human and nonhuman primates, with documented clinical efficacy. The hepatitis C virus (HCV)-chimpanzee model is the best available model for testing the immunotherapeutic effects of DCs in the setting of a chronic infection, as chimpanzees develop a persistent infection resembling that seen in humans. However, several reports have suggested that DCs derived from chronically infected individuals or nonhuman primates are functionally compromised. As a prelude to clinical studies, we evaluated whether functionally mature DCs could be generated in chimpanzee plasma by good manufacturing practice using CD14+ mononuclear precursors from chronically infected chimpanzees. DCs generated in a medium with HCV-negative plasma and treated with a defined cocktail of cytokines or a CD40 ligand trimer matured fully, as measured by the induction of CD83 expression and the upregulation of costimulatory molecules. Furthermore, the expression of CCR7 was induced, suggesting an acquisition of migration capacity. Mature DCs were capable of stimulating allogeneic T cells, antigen-specific memory CD4+ T cells, and HCV-specific CD8+-T-cell clones. In all cases, there was no evidence of HCV infection in DCs. Furthermore, these DCs maintained their phenotype and APC function after cryopreservation. Finally, no discernible differences were noted between DCs derived from HCV-infected and uninfected chimpanzees. In summary, precursor cells from HCV-infected chimpanzees are fully capable of differentiating into functional, mature DCs, which can now be reproducibly prepared for investigations of their immunotherapeutic potential in the setting of chronic HCV infection.

scholarly journals Differential Effects of Hepatitis C Virus JFH1 on Human Myeloid and Plasmacytoid Dendritic Cells

2009 ◽  
Vol 83 (11) ◽  
pp. 5693-5707 ◽  
Author(s):  
Hua Liang ◽  
Rodney S. Russell ◽  
Nicole L. Yonkers ◽  
David McDonald ◽  
Benigno Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Hcv Infection ◽  
Poly I:C ◽  
Dc Function ◽  
Cd40 Expression

ABSTRACT Dendritic cells (DCs) are reported to be functionally deficient during chronic hepatitis C virus (HCV) infection. Differing results have been reported on direct effects of intact replicative-form HCV on DC function. To better understand the effect of HCV on DC function, we treated freshly purified human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) with HCV JFH1. We found that HCV upregulated mDC maturation marker (CD83, CD86, and CD40) expression and did not inhibit Toll-like receptor 3 (TLR3) ligand [poly(I:C)]-induced mDC maturation, a finding consistent with the phenotype of DCs from HCV-infected subjects. At the same time, HCV JFH1 inhibited the ability of poly(I:C)-treated mDCs to activate naive CD4 T cells. In contrast, although there was no direct effect of virus on pDC maturation, HCV JFH1 inhibited TLR7 ligand (R848)-induced pDC CD40 expression, and this was associated with impaired ability to activate naive CD4 T cells. Parallel experiments with recombinant HCV proteins indicated HCV core protein may be responsible for a portion of the activity. Furthermore, HCV-mediated mDC maturation was dependent upon CD81-E2 interaction and, in part, TLR2. Using UV-treated HCV, we show that HCV-mediated mDC and pDC maturation is virus replication independent and, using strand specific PCR, we found no evidence for HCV replication within DCs. Because these effects of HCV on DC subset maturation and function in part recapitulate direct ex vivo analysis of DCs in chronic HCV infection, the mechanisms described here likely account for a portion of the DC subset defects observed in vivo.

scholarly journals Expression of hepatitis C virus-derived core or NS3 antigens in human dendritic cells leads to induction of pro-inflammatory cytokines and normal T-cell stimulation capabilities

2006 ◽  
Vol 87 (1) ◽  
pp. 61-72 ◽  
Author(s):  
Wen Li ◽  
Jie Li ◽  
D. Lorne J. Tyrrell ◽  
Babita Agrawal
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Responses ◽  
The Body ◽  
Cell Responses ◽  
Core Proteins ◽  
Chronic Hcv

The majority of hepatitis C virus (HCV)-infected individuals become chronically infected, which can result in liver cirrhosis and hepatocellular carcinoma. Patients with chronic HCV are unable to prime and maintain vigorous T-cell responses, which are required to rid the body of the viral infection. Dendritic cells (DCs) are the professional antigen-presenting cells that probably play a dominant role in priming and maintaining vigorous T-cell responses in HCV infection. Furthermore, inefficient DC function may play an important role in HCV chronicity. In order to determine the effect of HCV NS3 and core proteins on phenotype and function of human DCs, recombinant adenoviral vectors containing NS3 or core genes were used to infect human DCs. HCV NS3- or core-protein expression in DCs was confirmed by Western blotting and immunofluorescence staining. The DCs expressing HCV NS3 or core proteins expressed several inflammatory cytokine mRNAs, had a normal phenotype and effectively stimulated allogeneic T cells, as well as T cells specific for another foreign antigen (tetanus toxoid). These findings are important for rational design of cellular-vaccine approaches for the immunotherapy of chronic HCV.

scholarly journals Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

2021 ◽  
Vol 10 (2) ◽  
pp. 221
Author(s):  
Pil Soo Sung ◽  
Eui-Cheol Shin
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
De Novo ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Direct Acting

Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.

scholarly journals Abnormal Priming of CD4+ T Cells by Dendritic Cells Expressing Hepatitis C Virus Core and E1 Proteins

2002 ◽  
Vol 76 (10) ◽  
pp. 5062-5070 ◽  
Author(s):  
Pablo Sarobe ◽  
Juan José Lasarte ◽  
Noelia Casares ◽  
Ascensión López-Díaz de Cerio ◽  
Elena Baixeras ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Interleukin 2 ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Chronic Hcv ◽  
Antigen Presenting

ABSTRACT Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4+ T cells responding to HCV core in patients with chronic HCV infection. However, CD4+ response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4+ response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.

scholarly journals Hepatitis C Virus (HCV) Sequence Variation Induces an HCV-Specific T-Cell Phenotype Analogous to Spontaneous Resolution

2009 ◽  
Vol 84 (3) ◽  
pp. 1656-1663 ◽  
Author(s):  
Victoria Kasprowicz ◽  
Yu-Hoi Kang ◽  
Michaela Lucas ◽  
Julian Schulze zur Wiesch ◽  
Thomas Kuntzen ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Hcv Infection ◽  
Cell Phenotype ◽  
Cell Responses ◽  
Cognate Antigen ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT Hepatitis C virus (HCV)-specific CD8+ T cells in persistent HCV infection are low in frequency and paradoxically show a phenotype associated with controlled infections, expressing the memory marker CD127. We addressed to what extent this phenotype is dependent on the presence of cognate antigen. We analyzed virus-specific responses in acute and chronic HCV infections and sequenced autologous virus. We show that CD127 expression is associated with decreased antigenic stimulation after either viral clearance or viral variation. Our data indicate that most CD8 T-cell responses in chronic HCV infection do not target the circulating virus and that the appearance of HCV-specific CD127+ T cells is driven by viral variation.

scholarly journals Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression

2006 ◽  
Vol 81 (6) ◽  
pp. 2545-2553 ◽  
Author(s):  
Henry Radziewicz ◽  
Chris C. Ibegbu ◽  
Marina L. Fernandez ◽  
Kimberly A. Workowski ◽  
Kamil Obideen ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Viral Infections ◽  
T Cell Response ◽  
Hcv Infection ◽  
Interleukin 7 ◽  
Chronic Hcv Infection ◽  
Chronic Hcv

ABSTRACT The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

Genetic polymorphisms as the predictors of response to antiviral treatment in chronic hepatitis C virus infection

2011 ◽  
Vol 152 (22) ◽  
pp. 876-881
Author(s):  
Alajos Pár
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Polymorphisms ◽  
Chronic Hepatitis C ◽  
Genome Wide Association Study ◽  
Antiviral Treatment ◽  
Hcv Infection ◽  
Snp Analysis ◽  
Chronic Hcv

The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection. Orv. Hetil., 2011, 152, 876–881.

scholarly journals High Level of PD-1 Expression on Hepatitis C Virus (HCV)-Specific CD8+ and CD4+ T Cells during Acute HCV Infection, Irrespective of Clinical Outcome

2011 ◽  
Vol 85 (9) ◽  
pp. 4633-4633
Author(s):  
V. Kasprowicz ◽  
J. S. zur Wiesch ◽  
T. Kuntzen ◽  
B. E. Nolan ◽  
S. Longworth ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Clinical Outcome ◽  
Cd4 T Cells ◽  
Hcv Infection ◽  
Acute Hcv ◽  
High Level ◽  
Acute Hcv Infection
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