Dataset Information

Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells.

ABSTRACT: The cellular immune response contributes to viral clearance as well as to liver injury in acute and chronic hepatitis C virus (HCV) infection. An immunodominant determinant frequently recognized by liver-infiltrating and circulating CD8(+) T cells of HCV-infected patients is the HCV(NS3-1073) peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multiple cytokines, we were able to expand cytotoxic T cells specific for this determinant not only from the blood of 11 of 20 HCV-infected patients (55%) but also from the blood of 9 of 15 HCV-negative blood donors (60%), while a second HCV NS3 determinant was recognized only by HCV-infected patients and not by seronegative controls. The T-cell response of these healthy blood donors was mediated by memory T cells, which cross-reacted with a novel T-cell determinant of the A/PR/8/34 influenza A virus (IV) that is endogenously processed from the neuraminidase (NA) protein. Both the HCV NS3 and the IV NA peptide displayed a high degree of sequence homology, bound to the HLA-A2 molecule with high affinity, and were recognized by cytotoxic T lymphocytes with similar affinity (10(-8) M). Using the HLA-A2-transgenic mouse model, we then demonstrated directly that HCV-specific T cells could be induced in vivo by IV infection. Splenocytes harvested from IV-infected mice at the peak of the primary response (day 7 effector cells) or following complete recovery (day 21 memory cells) recognized the HCV NS3 peptide, lysed peptide-pulsed target cells, and produced gamma interferon. These results exemplify that host responses to an infectious agent are influenced by cross-reactive memory cells induced by past exposure to heterologous viruses, which could have important consequences for vaccine development.

SUBMITTER: Wedemeyer H

PROVIDER: S-EPMC114725 | biostudies-literature | 2001 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells.

Wedemeyer H H Mizukoshi E E Davis A R AR Bennink J R JR Rehermann B B

Journal of virology 20011201 23

The cellular immune response contributes to viral clearance as well as to liver injury in acute and chronic hepatitis C virus (HCV) infection. An immunodominant determinant frequently recognized by liver-infiltrating and circulating CD8(+) T cells of HCV-infected patients is the HCV(NS3-1073) peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multiple cytokines, we were able to expand cytotoxic T cells specific for this determinant not only from the blood of 11 of 20 H ...[more]

PMID: 11689620

Similar Datasets

Project description:Current seasonal influenza virus vaccines engender antibody-mediated protection that is hemagglutinin (HA) subtype specific and relatively short-lived. Coverage for other subtypes or even variants within a subtype could be improved from a better understanding of the factors that promote HA-specific antibody cross-reactivity. Current assays to evaluate cross-reactivity, such as the ELISA, require a separate test for each antigen and are neither high-throughput nor sample-sparing. To address this need, we produced an array of 283 purified HA proteins from influenza A virus subtypes H1 to H16 and H18 and influenza B virus. To evaluate performance, arrays were probed with sera from individuals before and after a booster dose of inactivated heterologous H5N1 vaccine and naturally infected cases at presentation and follow-up during the 2010 to 2011 influenza season, when H3N2 was prevalent. The response to the H5 vaccine boost was IgG only and confined to H5 variants. The response to natural H3N2 infection consisted of IgG and IgA and was reactive with all H3 variants displayed, as well as against other group 2 HA subtypes. In both groups, responses to HA1 proteins were subtype specific. In contrast, baseline signals were higher, and responses broader, against full-length HA proteins (HA1+HA2) compared to HA1 alone. We propose that these elevated baseline signals and breadth come from the recognition of conserved epitopes in the stalk domain by cross-reactive antibodies accumulated from previous exposure(s) to seasonal influenza virus. This array is a valuable high-throughput alternative to the ELISA for monitoring specificity and cross-reactivity of HA antibodies and has many applications in vaccine development.IMPORTANCE Seasonal influenza is a serious public health problem because the viral infection spreads easily from person to person and because of antigenic drift in neutralizing epitopes. Influenza vaccination is the most effective way to prevent the disease, although challenging because of the constant evolution of influenza virus subtypes. Our high-throughput protein microarrays allow for interrogation of subunit-specific IgG and IgA responses to 283 different HA proteins comprised of HA1 and HA2 domains as well as full-length HA proteins. This provides a tool that allows for novel insights into the response to exposure to influenza virus antigens. Data generated with our technology will enhance our understanding of the factors that improve the strength, breadth, and durability of vaccine-mediated immune responses and develop more effective vaccines.

Project description:Older people have difficulty controlling infection with common viruses such as influenza A virus (IAV), RNA virus which causes recurrent infections due to a high rate of genetic mutation, and Epstein Barr virus (EBV), DNA virus which persists in B cells for life in the 95% of people that become acutely infected. We questioned whether changes in epitope-specific memory CD8 T cell receptor (TCR) repertoires to these two common viruses could occur with increasing age and contribute to waning immunity. We compared CD8 memory TCR alpha and beta repertoires in two HLA-A2+ EBV- and IAV-immune donors, young (Y) and older (O) donors to three immunodominant epitopes known to be cross-reactive, IAV-M158-66 (IAV-M1), EBV-BMLF1280-288 (EBV-BM), and EBV-BRLF1109-117 (EBV-BR). We, therefore, also designed these studies to examine if TCR cross-reactivity could contribute to changes in repertoire with increasing age. TCR high throughput sequencing showed a significant difference in the pattern of TRBV usage between Y and O. However, there were many more differences in AV and AJ usage, between the age groups suggesting that changes in TCRα usage may play a greater role in evolution of the TCR repertoire emphasizing the importance of studying TRAV repertoires. With increasing age there was a preferential retention of TCR for all three epitopes with features in their complementarity-determining region (CDR3) that increased their ease of generation, and their cross-reactive potential. Young and older donors differed in the patterns of AV/AJ and BV/BJ pairings and usage of dominant CDR3 motifs specific to all three epitopes. Both young and older donors had cross-reactive responses between these 3 epitopes, which were unique and differed from the cognate responses having features that suggested they could interact with either ligand. There was an increased tendency for the classic IAV-M1 specific clone BV19-IRSS-JB2.7/AV27-CAGGGSQGNLIF-AJ42 to appear among the cross-reactive clones, suggesting that the dominance of this clone may relate to its cross-reactivity with EBV. These results suggest that although young and older donors retain classic TCR features for each epitope their repertoires are gradually changing with age, maintaining TCRs that are cross-reactive between these two common human viruses, one with recurrent infections and the other a persistent virus which frequently reactivates.

Project description:UnlabelledT 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 that in vitro HCV 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 an in vitro response 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.

Dataset Information

Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells.

Publications

Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets