Restoration of HCV-specific CD8+ T cell function by interferon-free therapy

Martin, Bianca; Hennecke, Nadine; Lohmann, Volker; Kayser, Antonin; Neumann‐Haefelin, Christoph; Kukolj, George; Böcher, W. O.; Thimme, Robert

doi:10.1016/j.jhep.2014.05.043

Cited by 215 publications

(232 citation statements)

References 27 publications

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“…3A, B). This is in contrast to recent literature on HCV-specific CD8 T cells and NK cells suggesting that both CD8 T cell [20] and NK-cell function [22], as well as NK-cell signaling [21], are restored upon IFN-free treatment. Instead, it appears that the insult inflicted by chronic HCVinfection to the MAIT cell compartment persists for a considerable time after the virus has been cleared.…”

contrasting

confidence: 99%

“…Our findings support a growing body of literature showing that MAIT cells are phenotypically activated and functionally depressed in settings of chronic infection and inflammation. Compared to HCV-specific CD8 T cells and NK cells, which both are to some extent reinvigorated upon successful viral elimination in chronic HCV-infection [20][21][22][23], the MAIT cell dysfunction appears to be nonreversible.…”

Section: Discussionmentioning

confidence: 99%

“…This remarkable outcome allows for studies on consequences on immune cell recovery following rapid pathogen removal. In such studies, it was recently shown that both HCVspecific CD8 T cell and NK-cell populations become reinvigorated following viral clearance [20][21][22][23]. However, whether MAIT cells recover upon HCV clearance remains unclear.…”

Section: Mucosal-associated Invariant T (Mait) Cells Are T Cells Withmentioning

confidence: 99%

“…1D). HCV-specific CD8T cells [20] and NK cells [22,23] have both been shown to restore their activated and exhausted phenotypes rapidly back to normal after IFN-free therapy. Our finding with sustained high expression of granzyme B and PD-1 suggests that MAIT cell reinvigoration may not occur despite successful elimination of the virus.…”

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confidence: 99%

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Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction Mucosal-associated invariant T (MAIT) cells are T cells with innate-like characteristics enriched in human liver and at mucosalCorrespondence: Dr. Niklas K. Björkström e-mail: niklas.bjorkstrom@ki.se sites [1,2]. They express a semi-invariant TCR carrying the Vα7.2 segment together with a restricted Vβ repertoire [1,2]. Upon activation, MAIT cells respond rapidly with cellular cytotoxicity as well as secretion of proinflammatory and anti-viral cytokines such * These authors contributed equally to this work. HCV is an extremely successful pathogen in that it establishes chronic infection in up to 90% of infected humans [9]. The reasons behind the failure of the human immune system to clear HCV are not fully understood but involve viral escape, CD4 and CD8 T-cell exhaustion, as well as NK-cell dysfunction [10][11][12] Until recently, pegylated IFN-α together with ribavirin was used to treat chronic HCV-infection. However, pegylated IFN-α in doses administered to patients has direct inhibitory effects on immune cells [15][16][17][18]. In the last years, treatment of HCV has undergone a revolution with the introduction of highly effective direct-acting antivirals (DAA) that rapidly eliminate the virus [19]. Thus, today the vast majority of patients clear HCV after such IFN-free treatment regimens. This remarkable outcome allows for studies on consequences on immune cell recovery following rapid pathogen removal. In such studies, it was recently shown that both HCVspecific CD8 T cell and NK-cell populations become reinvigorated following viral clearance [20][21][22][23]. However, whether MAIT cells recover upon HCV clearance remains unclear.Here, we performed a comprehensive analysis of MAIT cells in chronic HCV-infection. Specifically, we addressed whether MAIT cell recovery occurs upon HCV-clearance in patients receiving an IFN-free treatment regimen consisting of sofosbuvir and ribavirin. Strikingly, and in contrast to other immune cells, MAIT cells were not reinvigorated following successful HCV-clearance using IFNfree therapy. The results are discussed in relation to the current knowledge on human MAIT cell responses to other viral infections and in the context of immune exhaustion during chronic infections. Results and discussion MAIT cells are among the most severely affected immune cells in chronic HCV-infectionTo determine the impact of chronic HCV-infection on the peripheral blood immune cell compartment, we assessed the major myeloid and lymphoid immune cell subsets in a cohort of HCVpatients and healthy donors by using a 23-parameter flow cytometry staining approach as previously described [24] (Supporting Information Fig. 1). The major phenotype observed in chronic HCV was a severe loss of MAIT cells (Fig. 1A, B). Other immune cell alterations noted were in line with previous studies, including an increase in Tregs [25], a reduced frequency of pDCs [26], and a shift within the CD4...

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contrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mucosal-associated Invariant T (Mait) Cells Are T Cells Withmentioning

confidence: 99%

mentioning

confidence: 99%

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Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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“…Our case was unresponsive to Peg-IFN treatment against CHB, as she had HBV-DNA (less than 2000 IU/mL), Ani-Hbe, elevated liver enzymes due to CHC, and was in the immune tolerant phase of CHB [16]. Genotype D is prevalent in Turkey, although we have not analyzed the HBV genotype of our case [19]. HBs Ag seroclearance is very rarely seen as an annual rate of 2.4-3.2% with Peg-IFN treatment, and only <1% with nucleoside/nucleotide analogues [20].…”

Section: Discussionmentioning

confidence: 82%

Chronic Hepatitis B Reactivation Subsequent to Chronic Hepatitis C Treatment: A Case Report

Gedık¹,

Parcaoglu²

2017

J Hep

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Patients, who are coinfected with hepatitis B and C, are at high risk for a progression to severe liver disease (cirrhosis, decompensated liver disease), hepatocellular carcinoma, and unresponsiveness to treatment. In this article, a case who developed a reactivation of chronic hepatitis B subsequent to Chronic Hepatitis C (CHC) treatment is presented. A 42-year-old woman with HBV and HCV was admitted to infectious diseases clinic with a major complaint of fatigue for three months. Laboratory tests revealed an elevated alanine transaminase of 182 IU/L (Normal range: 0-55 IU/L), elevated aspartate transaminase of 150 IU/L, serum HCV-RNA levels of 2080195 IU/mL (genotype 1b), and HBV-DNA of 1184 IU/mL. The results of other laboratory tests were within the normal range and remained to be normal during the follow-up. Pegylated interferon alpha-2a (180 mcg/week) and ribavirin (1200 mg/day) were administered for the treatment of CHC for 48 weeks. After one year of CHC treatment, our case was admitted with the elevation in liver enzymes and HBV-DNA of 878215 IU/mL. The histopathological examination of liver tissue revealed a mildly active histologic activity (6/18) and a mildly active histological activity (1/6) according to ISHAK scoring. Tenofovir disoproxil tablet (245 mg/day) was initiated for the chronic hepatitis B treatment. The patient is followed up at the ambulatory clinic of infectious diseases. As a result, patients coinfected with HBV and HCV should be followed up for the reactivation of HBV after CHC treatment with either pegylated interferon-based therapy or oral direct-acting antiviral agents in the medium-term, and the cirrhosis and hepatocellular carcinoma in the long-term.

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Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection

Lemon¹,

Farci

Ghany

2009

The Liver

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Restoration of HCV-specific CD8+ T cell function by interferon-free therapy

Cited by 215 publications

References 27 publications

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Chronic Hepatitis B Reactivation Subsequent to Chronic Hepatitis C Treatment: A Case Report

Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection

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