Prediction of postembolization syndrome after transarterial chemoembolization of hepatocellular carcinoma and its impact on prognosis.

BACKGROUND: Postembolization syndrome (PES) represents the most frequent complication after transarterial chemoembolization (TACE) in patients with HCC. Given the vague definition as a symptom complex comprising abdominal pain, fever, and nausea, PES is diagnosed in heterogeneous patient cohorts with symptoms ranging from mild pain to severe deterioration of their general condition. This study aimed to evaluate predictive factors and the prognostic impact of PES with regard to different severity grades. METHODS: A total of 954 patients treated with TACE for HCC at the University Medical Centres Mainz and Freiburg were included in this study. PES disease severity was graded as mild, moderate, or severe according to a predefined combination of symptoms. Logistic regression models were used to identify independent predictors of PES. The prognostic impact of PES was evaluated by competing risk analyses considering liver transplantation as a competing risk. RESULTS: PES occurred in 616 patients (64.5%), but only 56 patients (5.9%) had severe PES, defined as moderate to severe abdominal pain requiring opioids in combination with fever and nausea. The largest tumor diameter was the strongest independent predictor of PES (OR = 1.21, 95% CI = 1.13-1.28), and severe PES (OR = 1.23, 95% CI = 1.14-1.33, p < 0.0001). Presence of liver cirrhosis was protective against PES (OR = 0.48, 95% CI = 0.27-0.84, p = 0.01). Furthermore, PES was independently associated with an impaired disease control rate (OR = 0.33, 95% CI = 0.16-0.69, p = 0.003) and severe PES with poor overall survival (subdistribution HR = 1.53, 95% CI = 0.99-2.36, p = 0.04). CONCLUSIONS: Tumor size and absence of liver cirrhosis are predictors of severe PES and associated with impaired prognosis in HCC patients after TACE.

SARS-CoV-2 and the liver: clinical and immunological features in chronic liver disease.

SARS-CoV-2 infection may affect the liver in healthy individuals but also influences the course of COVID-19 in patients with chronic liver disease (CLD). As described in healthy individuals, a strong SARS-CoV-2-specific adaptive immune response is important for the outcome of COVID-19, however, knowledge on the adaptive immune response in CLD is limited.Here, we review the clinical and immunological features of SARS-CoV-2 infection in individuals with CLD. Acute liver injury occurs in many cases of SARS-CoV-2 infection and may be induced by multiple factors, such as cytokines, direct viral infection or toxic effects of COVID-19 drugs. In individuals with CLD, SARS-CoV-2 infection may have a more severe course and promote decompensation and particularly in patients with cirrhosis. Compared with healthy individuals, the SARS-CoV-2-specific adaptive immune responses is impaired in patients with CLD after both, natural infection and vaccination but improves at least partially after booster vaccination.Following SARS-CoV-2 vaccination, rare cases of acute vaccine-induced liver injury and the development of autoimmune-like hepatitis have been reported. However, the concomitant elevation of liver enzymes is reversible under steroid treatment.

Decreased level of serum NT-proCNP associates with disease severity in COVID-19.

BACKGROUND: C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. METHODS: In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). RESULTS: The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. CONCLUSIONS: Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021.

Boosting compromised SARS-CoV-2-specific immunity with mRNA vaccination in liver transplant recipients.

BACKGROUND & AIMS: Liver transplant recipients (LTRs) demonstrate a reduced response to COVID-19 mRNA vaccination; however, a detailed understanding of the interplay between humoral and cellular immunity, especially after a third (and fourth) vaccine dose, is lacking. METHODS: We longitudinally compared the humoral, as well as CD4+ and CD8+ T-cell, responses between LTRs (n = 24) and healthy controls (n = 19) after three (LTRs: n = 9 to 16; healthy controls: n = 9 to 14 per experiment) to four (LTRs: n = 4; healthy controls: n = 4) vaccine doses, including in-depth phenotypical and functional characterization. RESULTS: Compared to healthy controls, development of high antibody titers required a third vaccine dose in most LTRs, while spike-specific CD8+ T cells with robust recall capacity plateaued after the second vaccine dose, albeit with a reduced frequency and epitope repertoire compared to healthy controls. This overall attenuated vaccine response was linked to a reduced frequency of spike-reactive follicular T helper cells in LTRs. CONCLUSION: Three doses of a COVID-19 mRNA vaccine induce an overall robust humoral and cellular memory response in most LTRs. Decisions regarding additional booster doses may thus be based on individual vaccine responses as well as evolution of novel variants of concern. IMPACT AND IMPLICATIONS: Due to immunosuppressive medication, liver transplant recipients (LTR) display reduced antibody titers upon COVID-19 mRNA vaccination, but the impact on long-term immune memory is not clear. Herein, we demonstrate that after three vaccine doses, the majority of LTRs not only exhibit substantial antibody titers, but also a robust memory T-cell response. Additional booster vaccine doses may be of special benefit for a small subset of LTRs with inferior vaccine response and may provide superior protection against evolving novel viral variants. These findings will help physicians to guide LTRs regarding the benefit of booster vaccinations.

SARS-CoV-2-Specific T Cell Responses in Immunocompromised Individuals with Cancer, HIV or Solid Organ Transplants.

Adaptive immune responses play an important role in the clinical course of SARS-CoV-2 infection. While evaluations of the virus-specific defense often focus on the humoral response, cellular immunity is crucial for the successful control of infection, with the early development of cytotoxic T cells being linked to efficient viral clearance. Vaccination against SARS-CoV-2 induces both CD4+ and CD8+ T cell responses and permits protection from severe COVID-19, including infection with the currently circulating variants of concern. Nevertheless, in immunocompromised individuals, first data imply significantly impaired SARS-CoV-2-specific immune responses after both natural infection and vaccination. Hence, these high-risk groups require particular consideration, not only in routine clinical practice, but also in the development of future vaccination strategies. In order to assist physicians in the guidance of immunocompromised patients, concerning the management of infection or the benefit of (booster) vaccinations, this review aims to provide a concise overview of the current knowledge about SARS-CoV-2-specific cellular immune responses in the vulnerable cohorts of cancer patients, people living with HIV (PLWH), and solid organ transplant recipients (SOT). Recent findings regarding the virus-specific cellular immunity in these differently immunocompromised populations might influence clinical decision-making in the future.

Liver-resident CD8+ T cells in viral hepatitis: not always good guys.

More than twenty years ago, non-HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells.

COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation.

Immunization with two mRNA vaccine doses elicits robust spike-specific CD8+ T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains unclear. Here we show that spike-specific CD8+ T cells are activated and expanded in all analyzed individuals receiving the 3rd and 4th mRNA vaccine shots. This CD8+ T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8+ T memory stem cell pool is not affected by the 3rd vaccination. Both 4th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8+ T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8+ T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.

SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis episodes have been described following SARS-CoV-2 infection and vaccination but their pathophysiology remains unclear. Herein, we report the case of a 52-year-old male, presenting with bimodal episodes of acute hepatitis, each occurring 2-3 weeks after BNT162b2 mRNA vaccination. We sought to identify the underlying immune correlates. The patient received oral budesonide, relapsed, but achieved remission under systemic steroids. METHODS: Imaging mass cytometry for spatial immune profiling was performed on liver biopsy tissue. Flow cytometry was performed to dissect CD8 T-cell phenotypes and identify SARS-CoV-2-specific and EBV-specific T cells longitudinally. Vaccine-induced antibodies were determined by ELISA. Data were correlated with clinical laboratory results. RESULTS: Analysis of the hepatic tissue revealed an immune infiltrate quantitatively dominated by activated cytotoxic CD8 T cells with panlobular distribution. An enrichment of CD4 T cells, B cells, plasma cells and myeloid cells was also observed compared to controls. The intrahepatic infiltrate showed enrichment for CD8 T cells with SARS-CoV-2-specificity compared to the peripheral blood. Notably, hepatitis severity correlated longitudinally with an activated cytotoxic phenotype of peripheral SARS-CoV-2-specific, but not EBV-specific, CD8+ T cells or vaccine-induced immunoglobulins. CONCLUSIONS: COVID-19 vaccination can elicit a distinct T cell-dominant immune-mediated hepatitis with a unique pathomechanism associated with vaccination-induced antigen-specific tissue-resident immunity requiring systemic immunosuppression. LAY SUMMARY: Liver inflammation is observed during SARS-CoV-2 infection but can also occur in some individuals after vaccination and shares some typical features with autoimmune liver disease. In this report, we show that highly activated T cells accumulate and are evenly distributed in the different areas of the liver in a patient with liver inflammation following SARS-CoV-2 vaccination. Moreover, within the population of these liver-infiltrating T cells, we observed an enrichment of T cells that are reactive to SARS-CoV-2, suggesting that these vaccine-induced cells can contribute to liver inflammation in this context.

SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individuals.

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

Survival prediction using the Freiburg index of post-TIPS survival (FIPS) in critically ill patients with acute- on chronic liver failure: A retrospective observational study.

Background and aim: Liver cirrhosis in patients treated in the intensive care unit (ICU) is associated with high mortality. Well established scores are useful to allow for assessment of prognosis and support ICU treatment guidance. However, currently used scoring systems often do not reflect the complexity of critically ill patients. Therefore, we tested the newly developed Freiburg index-of post-TIPS survival (FIPS) score in order to assess its potential role for prognostication of cirrhotic patients in the ICU. Methods: A total of 310 patients with liver cirrhosis treated in the ICU between 2010 and 2021 were enrolled in this retrospective observational study. Prognostic factors for mortality and 28-day mortality were assessed. Moreover, using c indices the prognostic discrimination of different prognostic scores was analyzed. Results: The FIPS score allowed to discriminate patients with high ICU mortality and within 28-days after ICU treatment (ICU mortality: 42.2 vs. 59.9%, p = 0.008 and 28-day mortality: 43.3 vs. 74.1%, p < 0.001). However, the FIPS score in its current composition showed no superior prognostic discrimination compared to other established scores. Multivariable analyses identified the FIPS score (HR 1.25 [1.04-1.49], p = 0.015) and lactate at admission (HR 1.07 [1.04-1.09], p < 0.001) as significant predictors of ICU mortality. Lactate at admission substantially improved patient risk stratification within each FIPS risk groups. Conclusion: Similar to other commonly used scores, the FIPS score in its current composition does not allow a sufficiently reliable prognostication of critically ill patients treated in the ICU. However, adding lactate as additional factor to the FIPS score may improve its prognostic ability.

Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants.

The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient's escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.

Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine.

SARS-CoV-2 spike mRNA vaccines1-3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4-6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival.

BACKGROUND & AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective and safe treatment for complications of portal hypertension. Survival prediction is important in these patients as they constitute a high-risk population. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation. METHODS: A total of 1,871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided into a training set (80% of study patients; n = 1,496) and a validation set (20% of study patients; n = 375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n = 290). Medical data and overall survival (OS) were assessed. A Cox regression model was used to create an alternative prediction model, which includes significant prognostic factors. RESULTS: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced median survival of 5.0 (3.1-6.9) months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9-5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh, MELD, MELD-Na score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation. CONCLUSIONS: The FIPS score is superior to established scoring systems for the identification of high-risk patients with a worse prognosis following elective TIPS implantation. LAY SUMMARY: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective treatment for patients with cirrhosis and clinically significant portal hypertension. However, risk stratification is a major challenge in these patients as currently available scoring systems have major drawbacks. Age, bilirubin, albumin and creatinine were included in a new risk score which was named the Freiburg index of post-TIPS survival (FIPS). The FIPS score can identify patients at high risk and may guide clinical decision making.

Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells.

Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.

[Viral Hepatitis: When to be Considered in Clinical Routine?] / Virushepatitis ­ wann daran denken?

Chronic viral hepatitis can remain unrecognized but may nevertheless lead to liver cirrhosis and hepatocellular carcinoma. Thus, patients with elevated liver enzymes as well as risk groups need to be screened and treated for viral hepatitis. These groups include, in particular, migrants from countries with high HBV or HCV prevalence, persons with previous or current intravenous drug use, and homosexual men. For HBV- or HCV-associated diseases, such as panarteriitis nodosa, cryoglobulinemic vasculitis or B-cell lymphoma, antiviral therapy may lead to remission. Prior to high-dose immunosuppressive therapy, especially with regimes containing rituximab, chronic or resolved HBV infection must be ruled out or antiviral prophylaxis may be required to avoid a potentially fatal HBV reactivation.

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load.

OBJECTIVE: A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. DESIGN: By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. RESULTS: HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. CONCLUSIONS: Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.

HCV-Specific T Cell Responses During and After Chronic HCV Infection.

Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field.

Differential virus-specific CD8+ T-cell epitope repertoire in hepatitis C virus genotype 1 versus 4.

Virus-specific CD8+ T-cell responses play an important role in the outcome of hepatitis C virus (HCV) infection. To date, most HCV-specific CD8+ T-cell epitopes have been defined in HCV genotype 1 infection. In contrast, the HCV genotype 4-specific CD8+ T-cell response is poorly defined. Here, we analysed whether known HCV-specific CD8+ T-cell epitopes are also recognized in HCV genotype 4-infected patients and set out to identify the first HCV genotype 4-specific CD8+ T-cell epitopes. We studied patients chronically infected with HCV genotype 1 (n = 20) or 4 (n = 21) using 91 well-described HCV-specific epitope peptides. In addition, we analysed 24 genotype 4-infected patients using 40 epitope candidates predicted using an in silico approach. HCV-specific CD8+ T-cell responses targeting previously described epitopes were detectable in the majority of genotype 1-infected patients (11 of 20). In contrast, patients infected with HCV genotype 4 rarely targeted these epitopes (4 of 21; P = .0247). Importantly, we were able to identify eight novel HCV genotype 4-specific CD8+ T-cell epitopes. Only one of these epitopes was shared between genotype 1 and genotype 4. These results indicate that there is little overlap between CD8+ T-cell repertoires targeting HCV genotype 1 and 4. Prophylactic vaccination studies based on HCV genotype 1 are currently underway. However, in countries with the highest prevalence of HCV infection, such as Egypt, most patients are infected with HCV genotype 4. Thus, prophylactic vaccination strategies need to be adapted to HCV genotype 4 before their application to regions where HCV genotype 4 is endemic.

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C.

Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.