Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients

Alanio, Cécile; Nicoli, Francesco; Sultanik, Philippe; Flecken, Tobias; Pérot, Brieuc P.; Duffy, Darragh; Bianchi, Elisabetta; Lim, Annick; Clave, Emmanuel; Buuren, Marit M. van; Schnuriger, Aurélie; Johnsson, Kerstin; Boussier, Jérémy; Garbarg‐Chenon, Antoine; Bousquet, Laurence; Mottez, Estelle; Schumacher, Ton N.; Toubert, Antoine; Appay, Victor; Heshmati, Farhad; Thimme, Robert; Pol, Stanislas; Mallet, Vincent; Albert, Matthew L.

doi:10.7554/elife.07916

Cited by 51 publications

(63 citation statements)

References 55 publications

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“…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 and CD8 T-cell compartments from naïve to antigen-experienced cells [27,28].…”

Section: Mait Cells Are Among the Most Severely Affected Immune Cellssupporting

confidence: 73%

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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Section: Mait Cells Are Among the Most Severely Affected Immune Cellssupporting

confidence: 73%

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

et al. 2016

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“…VEGF is known to be overexpressed in splanchnic organs from portal hypertensive animals, (31,32) and several factors present in patients with cirrhosis, that is, tissue hypoxia, cytokine imbalance, and shear stress, are known to promote VEGF expression. (33,34) Not surprisingly, HCC did not develop or recur in any patient Fig. 4.…”

Section: Discussionmentioning

confidence: 84%

“…This suggestion is consistent with the hypothesis put forward by Fernandez et al of VEGF‐driven splanchnic angiogenesis, based on findings in animals with portal hypertension and patients with cirrhosis. VEGF is known to be overexpressed in splanchnic organs from portal hypertensive animals, and several factors present in patients with cirrhosis, that is, tissue hypoxia, cytokine imbalance, and shear stress, are known to promote VEGF expression . Not surprisingly, HCC did not develop or recur in any patient with small varices or a low (<16 kPa) hepatic stiffness value during DAA treatment.…”

Section: Discussionmentioning

confidence: 92%

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

et al. 2018

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Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

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“…One recent analysis found that chronic HCV infection was associated with a 27% greater risk (hazard ratio 1.27, 95% confidence interval [CI] 1.18–1.37) of new‐onset chronic kidney disease (CKD) . The pathogenic mechanisms may include vasculitis (mixed cryoglobulinemia), chronic infection/inflammation through T‐cell dysregulation, and the effects of virally mediated diabetes and cardiovascular disease. In addition to mixed cryoglobulinemia, HCV infection is strongly associated with other glomerular diseases, such as membranoproliferative glomerulonephritis, membranous nephropathy, and polyarteritis nodosa …”

Section: Links Between Hcv and Ckd/esrdmentioning

confidence: 99%

Hepatitis C virus infection in patients with end‐stage renal disease

Wigneswaran¹,

Wyck

Pegues

et al. 2018

Hemodialysis International

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Chronic hepatitis C virus (HCV) infection is a major global health problem affecting 3-5 million people in the United States and over 100 million worldwide. Chronic HCV infection, which can lead to cirrhosis and hepatocellular carcinoma, also results in numerous other complications, including impairment of renal function. Because HCV is most often transmitted via parenteral exposure to blood or blood products, patients with end-stage renal disease (ESRD) treated with hemodialysis are at particular risk for infection. Historically, the medications available to treat HCV infection in these patients had significant side effects and were not particularly effective in generating a sustained virologic response. Since 2011, a number of direct-acting antiviral therapies have emerged that can lead to virological cure in the vast majority of patients, with low pill burden and few side effects. Here, we describe the biology and pathophysiology of HCV infection, and summarize current information on new therapies, with a particular focus on their application in patients with chronic kidney disease including ESRD.

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Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients

Cited by 51 publications

References 55 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

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

Hepatitis C virus infection in patients with end‐stage renal disease

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