CD4+ T cell restoration and control of hepatitis C virus replication after childbirth

Coss, Samantha; Torres-Cornejo, Almudena; Prasad, Mona; Moore‐Clingenpeel, Melissa; Grakoui, Arash; Lauer, Georg M.; Walker, Christopher M.; Honegger, Jonathan R.

doi:10.1172/jci123623

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…Interestingly, Coss et al could show an increase of CD4+ T cell functionality and number in a cohort of women after childbirth. This increase correlated with viral control, compared to women in their last trimester and women experiencing no viral control [110]. Previously the same group reported that the reduced viremia was associated with revived CD8+ T cell selection pressure on targeted epitopes [87].…”

Section: Failure Of Hcv-specific T Cell Responses In Chronic Hcv Infementioning

confidence: 75%

Adaptive Immune Response against Hepatitis C Virus

Kemming

Thimme

2020

IJMS

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A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.

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Section: Failure Of Hcv-specific T Cell Responses In Chronic Hcv Infementioning

confidence: 75%

Adaptive Immune Response against Hepatitis C Virus

Kemming

Thimme

2020

IJMS

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“…This has very recently also been documented for hepatitis C virus (HCV) infection. Individuals chronically infected with HCV showed an expansion of exhausted CD8 HCV-reactive T cells but lose their HCV-reactive CD4+ T cells over time, while individuals that clear the infection do not lose their HCV-reactive CD4+ T cells (30). Also, clearance of a chronic HCV infection, which may occur during pregnancy, was associated with the re-appearance of HCV-reactive CD4+ T cells (30).…”

Section: Discussionmentioning

confidence: 99%

“…Individuals chronically infected with HCV showed an expansion of exhausted CD8 HCV-reactive T cells but lose their HCV-reactive CD4+ T cells over time, while individuals that clear the infection do not lose their HCV-reactive CD4+ T cells (30). Also, clearance of a chronic HCV infection, which may occur during pregnancy, was associated with the re-appearance of HCV-reactive CD4+ T cells (30). Of note, the HCV-reactive CD4+ T cells expressed the exhaustion marker PD-1, which was interpreted as a sign of activation and differentiation rather than exhaustion (30).…”

Section: Discussionmentioning

confidence: 99%

Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation

et al. 2021

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Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.

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“…Interestingly, several studies have indicated that many persistently HCV-infected pregnant women achieve substantial decline in HCV viral load after childbirth, which is associated with re-appearance of HCV-specific CD4 + T cells with an effector-memory phenotype at 3 months postpartum [ 101 , 102 , 103 ]. In addition, significantly increased frequencies of IL-2 + , IFNγ + , and IL-2 + IFNγ + HCV-specific CD4 + T cells are detected at 3 months postpartum compared to the third trimester of pregnancy.…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

“…However, PD-1 expression on HCV-specific CD4 + T cells remained high and correlated with viral control, which is indicative of its role in CD4 + T cell activation rather than exhaustion in these cases. In contrast, reduced CTLA-4 expression was associated with higher viral control, indicating its role as a negative regulator of HCV-specific CD4 + T cell activity in the postpartum period [ 103 ]. Such studies indicate that revival of HCV-specific CD4 + T cell immunity is possible after persistent infection and it can play a crucial role in controlling HCV replication.…”

Section: Adaptive Immune Lymphocytes During and After Clearance Ofmentioning

confidence: 99%

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

Ghosh¹,

Romani²,

Kottilil³

et al. 2020

IJMS

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Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.

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CD4+ T cell restoration and control of hepatitis C virus replication after childbirth

Cited by 12 publications

References 22 publications

Adaptive Immune Response against Hepatitis C Virus

Adaptive Immune Response against Hepatitis C Virus

Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation

Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

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