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Background: Academic examination retakes are significant challenges in health professions education. With rigorous clinical assessments and high-stakes examinations, many students struggle to meet academic requirements, resulting in retakes. The voices and experiences of such students have often been absent within the broader discussion of health professions education. This study aimed to assess the impact and copying mechanisms of medical and nursing students with retakes across five Sub-Saharan African universities., Methods: This was a mixed-methods explanatory sequential study, integrating quantitative surveys and qualitative interviews. The study involved 764 medical and nursing clinical students from five universities across Sub Saharan Africa: Busitema University (Uganda), Mzuzu University (Malawi), University of Ibadan (Nigeria), Kwame Nkrumah University of Science and Technology (Ghana), and the University of Zambia. Quantitative data were analyzed using descriptive statistics. Qualitative data were explored through thematic analysis based on in-depth interviews with 15 purposively selected students who had experienced retakes., Results: Overall, the proportion of students who had ever had a retake in clinical assessments was 12.6%. Thematic analysis revealed emotional and psychological challenges, such as shock, anxiety, fear and suicidal thoughts particularly due to insufficient institutional support and lack of feedback. Many students also reported a perceived sense of unfairness in their assessments., Conclusions: The study highlights the multifaceted nature of retakes in health professions education in Sub-Saharan Africa. Recommendations for improvement include providing detailed feedback, transparency in assessments, and enhancing both academic and psychological support systems for students, particularly those at higher risk, such as older students and males. Further research is needed to investigate long-term academic and career outcomes and effective remediation strategies for students experiencing retakes., Competing Interests: Conflict of interest The authors declare no conflict of interest

Background: Academic examination retakes are significant challenges in health professions education. With rigorous clinical assessments, limited training resources and high-stakes examinations, students struggle to meet academic requirements which cab result in retakes. This study aimed to assess the proportion of medical and nursing students with retakes across five Sub-Saharan African universities and to explore factors contributing to the retakes., Methods: This was a cross-sectional quantitative study. The study involved 764 medical and nursing clinical students from five universities across Sub Saharan Africa: Busitema University (Uganda), Mzuzu University (Malawi), University of Ibadan (Nigeria), Kwame Nkrumah University of Science and Technology (Ghana), and the University of Zambia. Data was analyzed using descriptive statistics and logistic regression to identify factors associated with retakes., Results: Overall, the proportion of students who had ever had a retake in clinical assessments was 12.6%. Factors associated with retakes are age with students aged 25 and above showed a higher likelihood of failing compared to their younger counterparts (OR: 2.45, 95% CI: 1.06-5.64, P = 0.036) and gender with Male students more likely to get retakes compared to their female counterparts (OR: 1.91, 95% CI: 1.21-3.00, P = 0.005) at univariate, although this association was not statistically significant in multivariate analysis. OSCE was the most frequent examination format associated with retakes, accounting for 47.7% ( P < 0.001)., Conclusions: The present study brings to light the proportion of students who experienced retakes and the factors associated with retakes among health professions students in Sub-Saharan Africa. This highlights the need for institutional interventions targeting at-risk populations: older and male students, and those with assessment problems related to the different modes of assessing clinical skills. Amelioration of these factors through appropriate support systems could minimize the proportion of students having to retake modules and create a more supportive academic environment. Further research might focus on exploring the proportion of students experiencing retakes in each country and thus determine factors that could contribute to high stakes towards retakes for each country so as to develop country specific solution and improved clinical skills assessment., Competing Interests: Conflict of interest The authors declare no conflict of interest Additional Declarations: No competing interests reported.

Introduction: The development of a strong professional identity is influenced by the motivation behind enrolling in a nursing or midwifery programme. Professional identity is a driving force that sustains the commitment of nurses and midwives to nursing/midwifery and their dedication to the well‑being of those they serve. This study evaluated Ugandan students' reasons for enrolling in nursing and midwifery programmes. Furthermore, we investigated the nurse/midwifery practices that support professional identity creation in recent graduates and undergraduate nursing/midwifery students. Methods: A mixed‑method research approach was employed amongst nursing/midwifery students of Makerere University and Mbarara University of Science and Technology and recent nursing/midwifery graduates from Mulago National and Mbarara Regional referral hospitals. We collected quantitative data from 173 participants, and for qualitative data, we conducted six focus group discussions among recent graduates and students of nursing/midwifery. We used descriptive statistics and thematic analysis to analyse the quantitative and qualitative data. Results: Nearly all - 95.4% (165/173) - of the participants were motivated to undertake nursing/midwifery as their programme of study, and 94.2% (163/173) participants identified as nurses/midwives, all with an average score above 3. They also strongly agreed that they took up the programmes because they wanted to learn new things [111/173 (64.2%)] and considered nurses' groups important [68.8% (119/173)]. Participants proposed measures to promote the formation of professional identity among students and graduates, including the improvement of clinical education, the phasing out of certain levels of practice, the empowerment and embedding of ethical principles, recognition and motivation, mentorship, leadership, career guidance and the inclusion of men and challenging of gender stereotypes. Conclusion: Participants were motivated to work in nursing. The ways to promote professional identity included the improvement of clinical education, the phasing out of certain levels of practice, the empowerment and instillation of ethical principles, recognition and motivation, mentorship, leadership, career guidance and male inclusiveness and the challenging of gender stereotypes. Nursing and midwifery leadership needs to provide guidance, mentorship and empowerment; challenge gender stereotypes in nursing/midwifery practice; and give support while advocating for ethical practice., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background and Aims: The risk of developing HCC in chronically infected patients with AQ2 HCV with liver cirrhosis is significantly elevated. This risk remains high even after a sustained virological response with direct-acting antivirals. To date, disease-associated signatures of NK cells indicating HCC development are unclear., Approach and Results: This study investigated NK cell signatures and functions in 8 cohorts covering the time span of HCC development, diagnosis, and onset. In-depth analysis of NK cell profiles from patients with cirrhosis who developed HCC (HCV-HCC) after sustained virological response compared with those who remained tumor-free (HCV-noHCC) revealed increasingly dissimilar NK cell signatures over time. We identified expression patterns with persistently high frequencies of TIM-3 and CD38 on NK cells that were largely absent in healthy controls and were associated with a high probability of HCC development. Functional assays revealed that the NK cells had potent cytotoxic features. In contrast to HCV-HCC, the signature of HCV-noHCC converged with the signature found in healthy controls over time. Regarding tissue distribution, single-cell sequencing showed high frequencies of these cells in liver tissue and the invasive margin but markedly lower frequencies in tumors., Conclusions: We show that HCV-related HCC development has profound effects on the imprint of NK cells. Persistent co-expression of TIM-3hi and CD38 + on NK cells is an early indicator for HCV-related HCC development. We propose that the profiling of NK cells may be a rapid and valuable tool to assess the risk of HCC development in a timely manner in patients with cirrhosis after HCV cure., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Simulation is a new pedagogical method in Africa that underscores the need to operationalize it and generate context-specific scholarship regarding clinical simulation in Africa. Despite the superior learning outcomes of using simulation in medical education, its use in developing countries is often limited, compounded by limited scholarship on simulation especially relevant to an African context. The research aimed to explore perceptions surrounding the use of simulation among undergraduate students., Methods: A mixed method convergent parallel design was used in which both the quantitative and qualitative approaches were employed currently to explore the perception of the undergraduate students towards the use of clinical simulation in teaching and learning. The quantitative approach assessed the perception of the students on a five-point Likert from strongly disagree to strongly agree scale while the qualitative approach employed a focused group discussion to explore the perception of the students in regards to clinical simulation. Quantitative data was analyzed using Stata Version 17. Qualitative results were analyzed through thematic analysis by Brauna and Clark., Results: 298 participants were recruited into the study. The mean age of the participants was 27 years with a standard deviation of 5.81 years. The majority 152(51.01%) of the participants were males. Most 111(37.25%) of the participants were pursuing Bachelor of Medicine and Bachelor of Surgery. The grand mean of the perception scores of the students towards the use of simulation in clinical teaching was 3.875269 ±0.5281626. The participants strongly agreed that it is incredibly helpful to have someone who works in the field debrief with them after completing a scenario and their overall perception towards this was high (Mean =4.65241±0.6617337)., Conclusion: This exploratory study revealed that medical, nursing, and midwifery students from the rural Universities of Busitema and Lira demonstrated a positive perception of the use of clinical simulation in teaching and learning. The results conclude that simulations help students better understand concepts in clinical settings, provide them with valuable learning experiences, and help them stimulate critical thinking abilities. Further, the participants perceive simulation to be realistic, and knowledge gained could be transferred to the clinical areas., Competing Interests: Competing interests The authors declare no competing interests

Introduction: Experiences regarding the use of simulation in low-resource settings like Uganda where it has not taken root have not been explored. The purpose of the study was to explore the experiences of students, clinical staff, and faculty regarding the use of clinical simulation in teaching undergraduate students., Materials and Methods: The study was conducted at Busitema and Lira Universities in Uganda. We conducted 20 in-depth interviews with the faculty staff and 10 focused group discussions with undergraduate Nursing, Midwifery, Medical and Anesthesia students. The study obtained ethical clearance from the Busitema University Research and Ethics Committee (BUFHS-2023-78) and Uganda National Council of Science and Technology (HS3027ES). Thematic analysis was used to analyze the data., Results: Four themes emerged from the data. Simulation was seen to be about improvising and (return) demonstration. Concerns of realism were expressed including notions that simulation was not real, that simulation felt real and the extreme end that simulation tends to present the ideal setting. Perceived benefits of simulation include room for mistakes and immediate feedback, enhanced confidence and self-efficacy, enhanced acquisition of soft and clinical skills, prepares students for clinical placement, convenient and accessible. Concerns were expressed related to whether skills in clinical simulation would translate to clinical competence in the clinical setting., Conclusion: Students perceived simulation to be beneficial. However, concerns about realism and transferability of skills to clinical settings were noted. Clarifying preconceived notions against the use of clinical simulation will enhance its utilization in educational settings where simulation is not readily embraced., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests. Additional Declarations: No competing interests reported.

Background: A stable, well-functioning and integrated national medicines regulatory system is a core component of health systems resilient against infectious disease outbreaks. In many low- and middle-income countries, however, sizable gaps exist in the emergency preparedness framework of national regulatory authorities (NRAs). RegTrain-VaccTrain is a project of Germany Ministry of Health's Global Health Protection Programme that contributes to global efforts aimed at strengthening such regulatory systems by providing technical support and advice to partner NRAs. In this study, we probed the outputs of our capacity-strengthening activities for clinical trials oversight (CTO) to take stock of progress made and examine remaining priorities in order to provide specialized technical assistance in addressing them to improve operational readiness for emergencies., Method: Data validated from NRA self-benchmarking results in 2017 and worksheet records of November 2021 were utilized to assess the emergency preparedness capacity for CTO in three VaccTrain partner NRAs (Liberia, Sierra Leone, The Gambia) before and after interventional capacity-strengthening partnership, using specific public health emergency-related (sub-)indicators of the WHO Global Benchmarking Tool., Results: A generally weak and vulnerable structural framework for CTO characterized the emergency preparedness capacity in all three partner NRAs at baseline, thus putting their operational readiness for public health emergencies at risk. VaccTrain's collaborative work was successful at supporting individual NRAs to develop the full spectrum of operational structures (including (draft) regulations, guidelines, and standard operating procedures) required to improve regulatory preparedness. A gap in the formal approval and implementation of developed legal documents in two of three NRAs still remains. Notwithstanding, a robust emergency framework now exists and the NRAs stand better prepared to respond to (future) locally-concerning health emergencies, during which time clinical trials activity was observed to heighten., Conclusions: These results exemplify a north-south capacity-strengthening partnership model that effectively contributes in developing structures to enhance regulatory oversight and support expeditious product development in response to crises. They further underscore the equally critical role local/national processes play in facilitating the full implementation of developed structures., (© 2022. The Author(s).)

Background: Development of safe and efficacious medicines in many sub-Sahara African countries remains hampered due to fragmented health research infrastructure and ineffective regulatory oversight. To boost the latter in the area of Clinical Trials (CT) Oversight (CTO), many international programs and Regional Centers for Regulatory Excellence (RCORE) initiatives offer various trainings to help strengthen human resource capacity. Here, we aimed at evaluating the training outcomes (at home-institution level) of sponsored fellows for one of such capacity strengthening interventions; a measure that is less often reported and thus remains poorly understood., Method: The Global Health Protection Programme's VaccTrain project sponsored nine regulatory staff from eight National Medicines Regulatory Authorities (NMRAs) in sub-Saharan Africa for the RCORE CT Training Fellowship by FDA Ghana in a particular year. Using a systematized evaluation framework based on the theory of change, we assessed the individual- and NMRA-level achievement of pre-defined training outcomes. For this purpose, data was collected at pre-training and at short- and long-term evaluation time-points using a survey instrument., Results: At pre-training, our data revealed existence of differential expectations and orientations among the training participants, thus providing an early indication of potential distinctive patterns in achievement of desired training outcomes. In a short-term post-training follow-up evaluation, a two-group clustering of fellows based on the achievement of training outcomes where only one group (representing 44%) reported achievement of CTO-related outcomes was observed. At this time-point, achievement of training outcomes was associated with the vibrancy of CT activity and existence of a comprehensive technical structure for CTO. In a further long-term follow-up evaluation, our data revealed a successful achievement of CTO-related individual- and/or institutional-level outcomes in all but one fellow. Here again, availability of a robust technical structure for CTO (and perhaps fellow affiliation/selection)-but not CT vibrancy-showed a trend of temporal association with achievement of training outcomes., Conclusion: Given the pivotal role operational structures of international standards at home institutions play in translating training-acquired knowledge into measurable CTO-related outcomes, we encourage that capacity strengthening projects aimed at achieving health-related targets of Sustainable Development Goals adopt an approach built on this foundation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Owusu Sekyere, Škrnjug-Yudov, Pinz, Meyer and Conrad.)

Introduction: The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance., Objective: Here, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated., Methods: Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment., Results: Elevated pretherapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, signalling lymphocytic activation family 1, CCL11, FGF-5, LIF-R, interleukin 10 (IL-10), IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma-free patients experienced significant ameliorations., Conclusions: These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background & Aims: Hepatitis C virus (HCV)-specific CD8+ T cells are functionally impaired in chronic hepatitis C. Even though HCV can now be rapidly and sustainably cleared from chronically infected patients, the repercussions of HCV clearance on virus-specific CD8+ T cells remain elusive. Here, we aimed to investigate if HCV clearance by direct-acting antivirals (DAAs) could restore the functionality of exhausted HCV-specific CD8+ T cell responses., Methods: HCV-specific CD8+ T cells in peripheral blood were obtained from 40 patients with chronic HCV infection, during and 6 months following IFN-free DAA therapy. These cells were analyzed for comprehensive phenotypes, proliferation, cytokine production, mitochondrial fitness and response to immune-checkpoint blockade., Results: We show that, unlike activation markers that decreased, surface expression of multiple co-regulatory receptors on exhausted HCV-specific CD8+ T cells remained unaltered after clearance of HCV. Likewise, cytokine production by HCV-specific CD8+ T cells remained impaired following HCV clearance. The proliferative capacity of HCV multimer-specific CD8+ T cells was not restored in the majority of patients. Enhanced in vitro proliferative expansion of HCV-specific CD8+ T cells during HCV clearance was more likely in women, patients with low liver stiffness and low alanine aminotransferase levels in our cohort. Interestingly, HCV-specific CD8+ T cells that did not proliferate following HCV clearance could preferentially re-invigorate their proliferative capacity upon in vitro immune-checkpoint inhibition. Moreover, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cells could not be normalized after HCV clearance., Conclusion: Taken together, our data implies that exhausted HCV-specific CD8+ T cells remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients with chronic hepatitis C. Our results might have implications in cases of re-infection with HCV and for HCV vaccine development., Lay Summary: Direct-acting antiviral therapy results in cure of hepatitis C virus (HCV) in almost all treated patients. However, the impacts of HCV cure on immune responses remain controversial. Whether immune responses to HCV recover is important in cases of re-exposure, or for the resolution of extrahepatic manifestations. The main finding of our study was that HCV-specific T cells remain functionally impaired despite HCV clearance. This finding could explain the fact that HCV cure does not lead to protective immunity and that re-infections have frequently been observed., (Copyright © 2019. Published by Elsevier B.V.)

Objective: HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis., Design: PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology., Results: Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi-topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs - with evidence of IL-12 being a major culprit., Conclusion: Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.

Background & Aims: Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes., Methods: A comprehensive immune-phenotyping including investigation of 50 SIMs as well as ex-vivo phenotypes of NK-cells, CD3+, CD4+, CD8+ and regulatory T cells in 40 patients with viral and autoimmune chronic liver diseases was performed. The patients' cognitive functions were assessed using an extensive battery of neuropsychological testing., Results and Conclusion: Overall, our data indicate that while SIMs are significantly up-regulated, NK- and T-cells are less-activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background:  Hepatitis D virus (HDV) infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection., Methods:  Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used., Results:  Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8 + T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4 + and CD8 + T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells., Conclusions:  This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Hepatitis C virus (HCV) readily sets up persistence in a large fraction of infected hosts. Mounting epidemiological and immunological evidence suggest that HCV's persistence could influence immune responses toward unrelated pathogens and vaccines. Nonetheless, the fundamental contribution of the inflammatory milieu during persistent HCV infection in impacting immune cells specific for common pathogens such as CMV and EBV has not been fully studied. As the co-regulatory receptors PD-1, Tim-3, and 2B4 have all been shown to be vital in regulating CD8(+) T cell function, we assessed their expression on CMV/EBV-specific CD8(+) T cells from patients with chronic hepatitis C (CHC) and healthy controls ex vivo and upon stimulation with virus-specific peptides in vitro. Total and CMV/EBV-specific CD8(+) T cells expressing PD-1, Tim-3, and 2B4 were highly enriched in patients with CHC compared to healthy individuals ex vivo. In vitro peptide stimulation further potentiated the differential co-regulatory receptor expression of PD-1, Tim-3, and 2B4, which then culminated in an enhanced functionality of CMV/EBV-specific CD8(+) T cells in CHC patients. Comprehensively analyzing plasma cytokines between the two cohorts, we observed that not only was IFNα-2a dominant among 21 other inflammatory mediators elevated in CHC patients but it also correlated with PD-1 and Tim-3 expressions ex vivo. Importantly, IFNα-2a further caused upregulation of these markers upon in vitro peptide stimulation. Finally, we could prospectively study patients receiving novel IFN-free antiviral therapy. Here, we observed that treatment-induced clearance of HCV resulted in a partial reversion of the phenotype of CMV/EBV-specific CD8(+) T cells in patients with CHC. These data reveal an alteration of the plasma concentrations of IFNα-2a together with other inflammatory mediators during CHC, which appeared to pervasively influence co-regulatory receptor expression on CMV/EBV-specific CD8(+) T cells.

Background & Aims: The functionality of virus-specific T cells is regulated by a sophisticated network of an expanding repertoire of co-regulatory receptors, which could be harnessed for immunotherapeutic applications. However, targeting particular pathways during persistent virus infections has resulted in variable outcomes. The extent to which T cell exhaustion can be reversed, by targeting multiple co-regulatory pathways, still remains not fully investigated., Methods: We analysed the phenotype and in vitro functionality of HCV-specific CD8(+) T cells expressing PD-1, CTLA-4, TIM-3 or 2B4 either alone or in various combinations and compared expression levels to those of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) specific T cells in peripheral blood mononuclear cells (PBMCs) from the same cohort of patients with chronic hepatitis C (CHC) infection., Results: Blockade and/or crosslinking of distinct co-regulatory pathways in exhausted HCV-specific CD8(+) T cells resulted in rather diverse and individualized T cell responses, irrespective of the type and number of receptors targeted. Overall, in vitro manipulations of these pathways yielded three response possibilities: (i) total non-response (ii) good single blockade response and (iii) good dual/multiple blockade response, with each comprising approximately one-third of the patients tested. The diversity of the in vitro responsiveness of HCV-specific T cells was reflected by an enormous ex vivo phenotypic heterogeneity. Despite this broad heterogeneity, HCV-specific CD8(+) T cells differed from EBV- and CMV-specific T cells in particular by TIM-3 expression, which also correlated with liver disease activity and viral load., Conclusions: HCV-specific CD8(+) T cell functionality, upon co-regulatory receptor manipulations, was characterized by an individual pattern of responses in patients with CHC, suggesting that treatment approaches, targeting these receptors, should consider inter-individual differences and be personalized., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)