HCV NS5B (2594-2602) is an epitope of the non-structural protein 5B of Hepatitis C Virus. HCV NS5B contains CD8 + T cell epitopes that might be implicated in improvement of immunotherapeutic strategies for efficient vaccine development against HCV.
Applications of HCV NS5B (2594-2602)
HCV NS5B (2594-2602) is used to stimulate specific-cytotoxic T cell responses in peripheral blood mononuclear cells (PBMCs). Then, ELISPOT assay is used to quantify peptide epitope specificity and IFN-γ releasing effector cells.
HCV NS5B (2594-2602) was used as a candidate HCV antigen for vaccine development and CD8 + T cell responses against HCV NS5B (2594-2602) have been detected. Results of ELISPOT assay has shown HCV NS5B (2594-2602) -cytotoxic T cell responses in cells with HLA-A*02:01 type.
Potential cross-reactivity with HIV-1 p17 Gag (77-85)
Similarities between two HLA-A2-restricted epitopes of two viruses have been demonstrated: the amino acid sequence of HIV-1 p17 Gag (77-85) (SLYNTVATL) and of HCV NS5B (2594-2602) (ALYDVVTKL). Therefore, researches are conducted to know if during HCV/HIV co-infection it could be exist a T cell cross reactivity.
Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-gamma, a « stunned » phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.
2- Thimme R., Oldach D., Chang K. M., Steiger C., Ray S. C., Chisari F. V. J Exp Med. 194(10):1395-1496 (2001)
The virological and immunological features of hepatitis C virus (HCV) infection were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that progressed to chronicity while one subject cleared the virus. In all subjects, viremia was first detectable within 1-2 weeks of inoculation, 1 month or more before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged episode of acute hepatitis that coincided with a CD38+ IFN-gamma- CD8+ T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4+ T cell response emerged and the CD8+ T cells became CD38- and started producing IFN-gamma in response to HCV, coinciding with a rapid 100,000-fold decrease in viremia that occurred without a corresponding surge of disease activity. Chronic infection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4+ T cell responses that ultimately waned. In all subjects, viremia was higher at the peak of acute hepatitis than it was when the disease began, and the disease improved during the viremia. These results provide the first insight into the host-virus relationship in humans during the incubation phase of acute HCV infection, and they provide the only insight to date into the virological and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, the results suggest that the vigor and quality of the antiviral T cell response determines the outcome of acute HCV infection, that the ability of HCV to outpace the T cell response may contribute to its tendency to persist; that the onset of hepatitis coincides with the onset of the CD8+ T cell response, that disease pathogenesis and viral clearance are mediated by different CD8+ T cell populations that control HCV by both cytolytic and noncytolytic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.
3- Tan A. C. L., Eriksson E. M. Y., Kedzierska K., Deliyannis G., Valkenburg S.A., Zeng W. and Jackson D. C. Antiviral Research 94(2):168-178 (2012)
In hepatitis C virus (HCV) infection, CD8+ T cell responses have been shown to be important in viral clearance. Examining the efficacy of CD8+ T cell vaccines against HCV has been limited by the lack of an HCV infectious model in mice and the differences between MHC restriction in humans and mice. Using HLA-A2 transgenic HHD mice, we demonstrate that intranasally delivered Pam2Cys-based lipopeptides containing HLA-A2-restricted HCV epitopes can induce polyfunctional CD8+ T cell responses in several organs including the liver. To examine the activity of these responses in an infectious context, we developed a recombinant influenza virus that expresses the NS5B2594–2602 epitope from non-structural protein 5B of hepatitis C virus (PR8-HCVNS5B). We showed that mice inoculated with a lipopeptide containing the NS5B epitope had reduced viral loads following challenge with the PR8-HCVNS5B virus. This reduction was associated with the induction of NS5B2594–2602-specific IFN-γ and TNF-α co-producing CD8+ T cells. The T cell receptor usage in the NS5B2594–2602 response was found to exhibit a Vβ8.1/8.2 bias that was characterized by a narrow repertoire and a common CDR3β motif. This work has identified CD8+ T cell functions induced by lipopeptides that are associated with viral control and demonstrate the potential of lipopeptide-based vaccines as candidates for treatment of HCV infection.
The immunologic mechanisms underlying the faster progression of hepatitis C virus (HCV) disease in the presence of human immunodeficiency virus (HIV) coinfection are not clearly understood. T-cell cross-reactivity between HCV and influenza virus-specific epitopes has been associated with rapid progression of HCV disease (S. Urbani, B. Amadei, P. Fisicaro, M. Pilli, G. Missale, A. Bertoletti, and C. Ferrari, J. Exp. Med. 201:675-680, 2005). We asked whether T-cell cross-reactivity between HCV and HIV could exist during HCV/HIV coinfection and affect pathogenesis. Our search for amino acid sequence homology between the HCV and HIV proteomes revealed two similar HLA-A2-restricted epitopes, HIV-Gag (SLYNTVATL [HIV-SL9]) and HCV-NS5b (ALYDVVSKL [HCV-AL9]). We found that 4 out of 20 HLA-A2-positive (HLA-A2+) HIV-infected individuals had CD8+ T cells that recognized both the HIV-SL9 and HCV-AL9 epitopes. However, the AL9 epitope was generally shown to be a weak agonist. Although HCV-monoinfected individuals in our study did not show AL9-specific responses, we found that about half of HCV/HIV-coinfected individuals had dual responses to both epitopes. High dual T-cell recognition among coinfected subjects was usually due to separate T-cell populations targeting each epitope, as determined by pentamer staining. The one individual demonstrating cross-reactive T cells to both epitopes showed the most advanced degree of liver disease. In coinfected individuals, we observed a positive correlation between the magnitudes of T-cell responses to both the SL9 and the AL9 epitopes, which was also positively associated with the clinical parameter of liver damage. Thus, we find that HIV infection induces T cells that can cross-react to heterologous viruses or prime for T cells that are closely related in sequence. However, the induction of cross-reactive T cells may not be associated with control of disease caused by the heterologous virus. This demonstrates that degeneracy of HIV-specific T cells may play a role in the immunopathology of HCV/HIV coinfection.
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