scholarly journals Strain-Specific T-Cell Suppression and Protective Immunity in Patients with Chronic Hepatitis C Virus Infection

2005 ◽  
Vol 79 (11) ◽  
pp. 6976-6983 ◽  
Author(s):  
Kazushi Sugimoto ◽  
David E. Kaplan ◽  
Fusao Ikeda ◽  
Jin Ding ◽  
Jonathan Schwartz ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Genotype 2

ABSTRACT Hepatitis C virus (HCV) frequently persists with an apparently ineffective antiviral T-cell response. We hypothesized that some patients may be exposed to multiple HCV subtypes and that strain-specific T cells could contribute to the viral dynamics in this setting. To test this hypothesis, CD4 T-cell responses to three genotype 1a-derived HCV antigens and HCV antibody serotype were examined in chronically HCV infected (genotypes 1a, 1b, 2, 3, and 4) and spontaneously HCV recovered subjects. Consistent with multiple HCV exposure, 63% of patients infected with genotypes 2 to 4 (genotypes 2-4) and 36% of those infected with genotype 1b displayed CD4 T-cell responses to 1a-derived HCV antigens, while 29% of genotype 2-4-infected patients showed serotype responses to genotype 1. Detection of 1a-specific T cells in patients without active 1a infection suggested prior self-limited 1a infection with T-cell-mediated protection from 1a but not from non-1a viruses. Remarkably, CD4 T-cell responses to 1a-derived HCV antigens were weakest in patients with homologous 1a infection and greater in non-1a-infected patients: proportions of patients responding were 19% (1a), 36% (1b), and 63% (2-4) (P = 0.0006). Increased 1a-specific CD4 T-cell responsiveness in non-1a-infected patients was not due to increased immunogenicity or cross-reactivity of non-1a viruses but directly related to sequence divergence. We conclude that the T-cell response to the circulating virus is either suppressed or not induced in a strain-specific manner in chronically HCV infected patients and that, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist. These findings provide new insights into host-virus interactions in HCV infection that have implications for vaccine development.

scholarly journals Hepatitis C Virus Induces Regulatory T Cells by Naturally Occurring Viral Variants to Suppress T Cell Responses

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Matthew F. Cusick ◽  
Jennifer J. Schiller ◽  
Joan C. Gill ◽  
David D. Eckels
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cell Responses ◽  
Naturally Occurring ◽  
Specific Manner

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3358-375in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3358-375-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence.

scholarly journals Broadening CD4+ and CD8+ T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

2017 ◽  
Vol 91 (14) ◽  
Author(s):  
Jonathan Filskov ◽  
Marianne Mikkelsen ◽  
Paul R. Hansen ◽  
Jan P. Christensen ◽  
Allan R. Thomsen ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Recombinant Protein ◽  
T Cell Responses ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Vaccine Approach

ABSTRACT Despite the introduction of effective drugs to treat patients with chronic hepatitis C virus (HCV) infection, a vaccine would be the only means to substantially reduce the worldwide disease burden. An incomplete understanding of how HCV interacts with its human host and evades immune surveillance has hampered vaccine development. It is generally accepted that in infected individuals, a narrow repertoire of exhausted T cells is a hallmark of persistent infection, whereas broad, vigorous CD4+ and CD8+ T cell responses are associated with control of acute hepatitis C. We employed a vaccine approach based on a mixture of peptides (pepmix) spanning the entire sequence of HCV nonstructural protein 3 (NS3) in cross-priming cationic liposomes (CAF09) to facilitate a versatile presentation of all possible T cell epitopes, regardless of the HLA background of the vaccine recipient. Here, we demonstrate that vaccination of mice with NS3 pepmix broadens the repertoire of epitope-specific T cells compared to the corresponding recombinant protein (rNS3). Moreover, vaccination with rNS3 induced only CD4+ T cells, whereas the NS3 pepmix induced a far more vigorous CD4+ T cell response and was as potent a CD8+ T cell inducer as an adenovirus-vectored vaccine expressing NS3. Importantly, the cellular responses are dominated by multifunctional T cells, such as gamma interferon-positive (IFN-γ+) tumor necrosis factor alpha-positive (TNF-α+) coproducers, and displayed cytotoxic capacity in mice. In conclusion, we present a novel vaccine approach against HCV, inducing a broadened T cell response targeting both immunodominant and potential subdominant epitopes, which may be key elements to counter T cell exhaustion and prevent chronicity. IMPORTANCE With at least 700,000 annual deaths, development of a vaccine against hepatitis C virus (HCV) has high priority, but the tremendous ability of the virus to dodge the human immune system poses great challenges. Furthermore, many chronic infections, including HCV infection, have a remarkable ability to drive initially strong CD4+ and CD8+ T cell responses against dominant epitopes toward an exhausted, dysfunctional state. Thus, new and innovative vaccine approaches to control HCV should be evaluated. Here, we report on a novel peptide-based nanoparticle vaccine strategy (NS3 pepmix) aimed at generating T cell immunity against potential subdominant T cell epitopes that are not efficiently targeted by vaccination with full-length recombinant protein (rNS3) or infection with HCV. As proof of concept, we found that NS3 pepmix excels in broadening the repertoire of epitope-specific, multifunctional, and cytotoxic CD4+ and CD8+ T cells compared to vaccination with rNS3, which generated only CD4+ T cell responses.

scholarly journals Frequency, Private Specificity, and Cross-Reactivity of Preexisting Hepatitis C Virus (HCV)-Specific CD8+T Cells in HCV-Seronegative Individuals: Implications for Vaccine Responses

2015 ◽  
Vol 89 (16) ◽  
pp. 8304-8317 ◽  
Author(s):  
Shihong Zhang ◽  
Rakesh K. Bakshi ◽  
Pothakamuri Venkata Suneetha ◽  
Paraskevi Fytili ◽  
Dinler A. Antunes ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Memory Cells ◽  
Cell Responses

ABSTRACTT cell responses play a critical role in controlling or clearing viruses. Therefore, strategies to prevent or treat infections include boosting T cell responses. T cells specific for various pathogens have been reported in unexposed individuals and an influence of such cells on the response toward vaccines is conceivable. However, little is known about their frequency, repertoire, and impact on vaccination. We performed a detailed characterization of CD8+T cells specific to a hepatitis C virus (HCV) epitope (NS3-1073) in 121 HCV-seronegative individuals. We show thatin vitroHCV NS3-1073-specific CD8+T cell responses were rather abundantly detectable in one-third of HCV-seronegative individuals irrespective of risk factors for HCV exposure.Ex vivo, these NS3-1073-specific CD8+T cells were found to be both naive and memory cells. Importantly, recognition of various peptides derived from unrelated viruses by NS3-1073-specific CD8+T cells showed a considerable degree of T cell cross-reactivity, suggesting that they might in part originate from previous heterologous infections. Finally, we further provide evidence that preexisting NS3-1073-specific CD8+T cells can impact the T cell response toward peptide vaccination. Healthy, vaccinated individuals who showed anin vitroresponse toward NS3-1073 already before vaccination displayed a more vigorous and earlier response toward the vaccine.IMPORTANCEPreventive and therapeutic vaccines are being developed for many viral infections and often aim on inducing T cell responses. Despite effective antiviral drugs against HCV, there is still a need for a preventive vaccine. However, the responses to vaccines can be highly variable among different individuals. Preexisting T cells in unexposed individuals could be one reason that helps to explain the variable T cell responses to vaccines. Based on our findings, we suggest that HCV CD8+T cells are abundant in HCV-seronegative individuals but that their repertoire is highly diverse due to the involvement of both naive precursors and cross-reactive memory cells of different specificities, which can influence the response to vaccines. The data may emphasize the need to personalize immune-based therapies based on the individual's T cell repertoire that is present before the immune intervention.

scholarly journals Comprehensive Analysis of CD8+-T-Cell Responses against Hepatitis C Virus Reveals Multiple Unpredicted Specificities

2002 ◽  
Vol 76 (12) ◽  
pp. 6104-6113 ◽  
Author(s):  
Georg M. Lauer ◽  
Kei Ouchi ◽  
Raymond T. Chung ◽  
Tam N. Nguyen ◽  
Cheryl L. Day ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cell Response ◽  
Critical Role ◽  
T Cell Responses ◽  
Comprehensive Analysis ◽  
T Cell Response ◽  
Hcv Infection ◽  
Cell Responses

ABSTRACT The hepatitis C virus (HCV)-specific CD8+-T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8+-T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8+-T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8+-T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition.

Analysis of EBV-Specific T Cell Responses in Transplant Recipients with PTLD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1915-1915
Author(s):  
Kathrin Sebelin ◽  
Antje Meier ◽  
Matthias Papp-Vary ◽  
Stefan Oertel ◽  
Antonio Pezzutto ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cell Response ◽  
Low Frequency ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract EBV causes a chronic infection in >95 % of the population and despite its strong growth transforming capacity the majority of EBV infected individuals remain asymptomatic. In contrary, in immunosuppressed patients (pts) the risk of EBV reactivation and development of posttransplant lymphoproliferative disease (PTLD) is high. This is assumed to be due to a defective T cell response. Here we analyzed the EBV-specific CD8 and CD4 T cell response to different EBV latent and lytic antigens in pts with newly diagnosed PTLD. A prospective study of 10 pts after solid organ transplantation at time of diagnosis of PTLD was performed. EBV-specific CD8 T cells were examined by flow cytometric analysis using HLA-A2, HLA-B7 and HLA-B8 restricted tetramers incorporating BMLF1 (lytic), EBNA3 and LMP2 (both latent)-derived peptides. Staining was done in conjunction with mAbs against CD8 and CCR7. The ability of CD8 T cells to produce IFN-γ in response to the same EBV-derived peptides was measured by cytokine secretion assay. In healthy, EBV+ donors, we previously have found a consistent CD4 T cell response to the latent EBV antigen EBNA1. Therefore, EBNA1-specific CD4 T cell responses were monitored for IFN-g / IL-4 secretion after protein stimulation. T cell analysis was combined with EBV-DNA quantiation by real time PCR. We found EBV-specific CD8 T cell responses at low frequency in most pts with PTLD (8/10). Half of the pts showed low frequency EBNA1 specific CD4+ T cell responses. All pts with an EBNA1 specific CD4 T cell response showed an EBV-specific CD8 T cell response. In 2/10 pts we found no EBV-specific CD4 and CD8 T cell responses and both pts died under initial therapy. EBV-viral load was found to inversely correlate to absolute CD4 T cell counts. In comparison to healthy normal donors, no significant differences in EBV-specific T cell response could be observed. However, pts EBV-specific T cells were decreased in comparison to pts with high EBV viral load after TX and no PTLD as well as in comparison to pts with infectious mononucleosis. These results indicate that impairment of EBV-specific T cells is not due to clonal depletion, but rather seems to be due to impaired functional activation and expansion. We therefore conclude that pts with PTLD have an inadequatly low EBV-specific T cell responses which correlates to a low absolute CD4 T cell count. We propose a combined immunomonitoring of EBV viral load, absolute CD4 T cell count and EBV-specific T cell enumeration in pts at risk for development of PTLD. Further studies are needed to evaluate the role of EBV-specific T cell monitoring in immunosuppressed pts for prediction of PTLD and the potential usefulness of T cell monitoring as a prognostic marker in PTLD.

Analysis of HIV-1–  and CMV-specific memory CD4 T-cell responses during primary and chronic infection

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1381-1387 ◽  
Author(s):  
Alexandre Harari ◽  
G. Paolo Rizzardi ◽  
Kim Ellefsen ◽  
Donatella Ciuffreda ◽  
Patrick Champagne ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cmv Infection ◽  
Cell Responses ◽  
Specific Memory ◽  
Hiv 1

CD4 T-cell–specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1– and CMV-specific interferon-γ–secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1–specific CD4 T-cell responses. A substantial proportion of CD4+CCR7− T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

scholarly journals Preservation of Intrahepatic Hepatitis C Virus (HCV)–Specific CD4+T Cell Responses despite Global Loss of CD4+T Cells in HCV/HIV Coinfection

2007 ◽  
Vol 196 (4) ◽  
pp. 577-586 ◽  
Author(s):  
Chihiro Morishima ◽  
Margaret C. Shuhart ◽  
Christina S. Yoshihara ◽  
Denise M. Paschal ◽  
Melissa A. Silva ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Hiv Coinfection

The magnitude and breadth of hepatitis C virus–specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1170-1178 ◽  
Author(s):  
Arthur Y. Kim ◽  
Georg M. Lauer ◽  
Kei Ouchi ◽  
Marylyn M. Addo ◽  
Michaela Lucas ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Hiv 1

AbstractCD8+ T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4+ T-helper cells. To determine the relationship between HIV-1–induced CD4+ T-cell depletion and hepatitis C virus (HCV)–specific CD8+ T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8+ T-cell responses to the entire HCV polyprotein were determined by using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1–associated CD4+ depletion was associated with significantly lower HCV-specific CD8+ T cells (R = 0.48, P < .0001). In contrast, declining CD4+ counts over the same range were not associated with diminished Epstein-Barr virus (EBV)– (R = 0.19, P = .31) or HIV-1–specific (R = –0.13, P = .60) CD8+ T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8+ T-cell responses are sensitive to absolute CD4+ T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

447 Reinfection with the hepatitis C virus: Kinetics of viral clearance and multi-parameter analysis of CD4+ T-cell response

2006 ◽  
Vol 44 ◽  
pp. S167 ◽  
Author(s):  
L. Weseslindtner ◽  
J.H. Aberle ◽  
C. Gurguta ◽  
P. Steindl-Munda ◽  
T. Popow-Kraupp ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Viral Clearance ◽  
Parameter Analysis ◽  
Cd4 T Cell ◽  
Kinetics Of
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