scholarly journals Kinetic Analysis by Real-Time PCR of Hepatitis C Virus (HCV)-Specific T Cells in Peripheral Blood and Liver after Challenge with HCV

2008 ◽  
Vol 82 (21) ◽  
pp. 10487-10492 ◽  
Author(s):  
Ramesh K. Ramalingam ◽  
Dirk Meyer-Olson ◽  
Naglaa H. Shoukry ◽  
David G. Bowen ◽  
Christopher M. Walker ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Real Time ◽  
Real Time Pcr ◽  
Peripheral Blood ◽  
Hcv Infection ◽  
Virus Challenge ◽  
Rapid Kinetics

ABSTRACT Intrahepatic virus-specific CD8+ T cells are thought to be important for the control of hepatitis C virus (HCV) infection, yet the precise kinetics for the expansion of epitope-specific T cells over the course of infection are difficult to determine with currently available methods. We used a real-time PCR assay to measure the frequency of clonotypic HCV-specific CD8+ T cells in peripheral blood and snap-frozen liver biopsy specimens of two chimpanzees (Pan troglodytes) with previously resolved HCV infection who were rechallenged with HCV. In response to rechallenge, the magnitude of each clonotypic response was 10-fold higher in the liver than in the blood, and the peak clonotype frequency was concurrent with the peak viral load. The higher frequency of HCV-specific clonotypes in the liver than in peripheral blood was maintained for at least 3 months after the clearance of viremia. After antibody-mediated CD8+ T-cell depletion and another viral challenge, the rebound of these clonotypes was seen prior to an appreciable reconstitution of CD8+ T-cell values and, again, at higher frequencies in the liver than in peripheral blood. These data demonstrate the importance of intrahepatic virus-specific CD8+ T cells for the clearance of infection and the rapid kinetics of expansion after virus challenge.

scholarly journals Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection

2008 ◽  
Vol 82 (20) ◽  
pp. 9808-9822 ◽  
Author(s):  
Henry Radziewicz ◽  
Chris C. Ibegbu ◽  
Huiming Hon ◽  
Melissa K. Osborn ◽  
Kamil Obideen ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Chronic Phase ◽  
T Cell Response ◽  
Hcv Infection ◽  
Caspase 9 ◽  
Acute Hcv ◽  
Acute Hcv Infection

ABSTRACT A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.

scholarly journals Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 683 ◽  
Author(s):  
David Wolski ◽  
Georg M. Lauer
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Differentiation ◽  
Hcv Infection ◽  
Early Gene ◽  
Human Model

The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses.

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 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

2007 ◽  
Vol 82 (6) ◽  
pp. 3154-3160 ◽  
Author(s):  
Victoria Kasprowicz ◽  
Julian Schulze zur Wiesch ◽  
Thomas Kuntzen ◽  
Brian E. Nolan ◽  
Steven Longworth ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Clinical Outcome ◽  
Acute Infection ◽  
Hcv Infection ◽  
Chronic Infections ◽  
Acute Hcv ◽  
High Level

ABSTRACT We monitored expression of PD-1 (a mediator of T-cell exhaustion and viral persistence) on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells from blood and liver during acute and chronic infections and after the resolved infection stage. PD-1 expression on HCV-specific T cells was high early in acute infection irrespective of clinical outcome, and most cells continued to express PD-1 in resolved and chronic stages of infection; intrahepatic expression levels were especially high. Our results suggest that an analysis of PD-1 expression alone is not sufficient to predict infection outcome or to determine T-cell functionality in HCV infection.

scholarly journals Viral Sequence Evolution in Acute Hepatitis C Virus Infection

2007 ◽  
Vol 81 (21) ◽  
pp. 11658-11668 ◽  
Author(s):  
Thomas Kuntzen ◽  
Joerg Timm ◽  
Andrew Berical ◽  
Lia L. Lewis-Ximenez ◽  
Andrea Jones ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Consensus Sequence ◽  
T Cell Responses ◽  
Hcv Infection ◽  
Sequence Evolution ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT CD8+-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+-T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total nonenvelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of nonenvelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.

scholarly journals Hepatitis C Virus Affects Tuberculosis-Specific T Cells in HIV-Negative Patients

Viruses ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 101 ◽  
Author(s):  
Mohamed Ahmed El-Mokhtar ◽  
Sherein G. Elgendy ◽  
Abeer Sharaf Eldin ◽  
Elham Ahmed Hassan ◽  
Ali Abdel Azeem Hasan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cd4 T Cells ◽  
Hcv Infection ◽  
Hla Dr ◽  
Ifn Γ ◽  
The Impact

The occurrence of tuberculosis (TB) and hepatitis C virus (HCV) infections in the same patient presents a unique clinical challenge. The impact of HCV infection on the immune response to TB remains poorly investigated in TB+/HCV+ patients. This study was conducted to evaluate the impact of HCV on the T-cell-mediated immune response to TB in coinfected patients. Sixty-four patients with active TB infections were screened for coinfection with HCV. The expression of immune activation markers IFN-γ, CD38, and HLA-DR on TB-specific CD4+ T cells was evaluated by flow cytometry in TB-monoinfected patients, TB/HCV-coinfected patients, and healthy controls. IL-2, IL-4, IFN-γ, TNF-α, and IL-10 levels were measured using ELISA. The end-of-treatment response to anti-TB therapy was recorded for both patient groups. Significantly lower levels of CD4+IFN-γ+CD38+ and CD4+IFN-γ+HLA-DR+ T cells were detected in TB/HCV-coinfected patients compared to TB monoinfected patients and controls. TB+/HCV+-coinfected patients showed higher serum levels of IL-10. The baseline frequencies of TB-specific activated T-cell subsets did not predict the response to antituberculous therapy in TB+/HCV+ patients. We concluded that different subsets of TB-specific CD4+ T cells in TB/HCV-infected individuals are partially impaired in early-stage HCV infection. This was combined with increased serum IL-10 level. Such immune modulations may represent a powerful risk factor for disease progression in patients with HCV/TB coinfection.

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.

scholarly journals Analysis of CD127 and KLRG1 Expression on Hepatitis C Virus-Specific CD8+ T Cells Reveals the Existence of Different Memory T-Cell Subsets in the Peripheral Blood and Liver

2006 ◽  
Vol 81 (2) ◽  
pp. 945-953 ◽  
Author(s):  
Bertram Bengsch ◽  
Hans Christian Spangenberg ◽  
Nadine Kersting ◽  
Christoph Neumann-Haefelin ◽  
Elisabeth Panther ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Peripheral Blood ◽  
Expression Profiles ◽  
Large Fraction ◽  
Killer Cell ◽  
Cell Receptor ◽  
T Cell Subsets

ABSTRACT The differentiation and functional status of virus-specific CD8+ T cells is significantly influenced by specific and ongoing antigen recognition. Importantly, the expression profiles of the interleukin-7 receptor alpha chain (CD127) and the killer cell lectin-like receptor G1 (KLRG1) have been shown to be differentially influenced by repetitive T-cell receptor interactions. Indeed, antigen-specific CD8+ T cells targeting persistent viruses (e.g., human immunodeficiency virus and Epstein-Barr virus) have been shown to have low CD127 and high KLRG1 expressions, while CD8+ T cells targeting resolved viral antigens (e.g., FLU) typically display high CD127 and low KLRG1 expressions. Here, we analyzed the surface phenotype and function of hepatitis C virus (HCV)-specific CD8+ T cells. Surprisingly, despite viral persistence, we found that a large fraction of peripheral HCV-specific CD8+ T cells were CD127+ and KLRG1− and had good proliferative capacities, thus resembling memory cells that usually develop following acute resolving infection. Intrahepatic virus-specific CD8+ T cells displayed significantly reduced levels of CD127 expression but similar levels of KLRG1 expression compared to the peripheral blood. These results extend previous studies that demonstrated central memory (CCR7+) and early-differentiated phenotypes of HCV-specific CD8+ T cells and suggest that insufficient stimulation of virus-specific CD8+ T cells by viral antigen may be responsible for this alteration in HCV-specific CD8+ T-cell differentiation during chronic HCV infection.

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