Hepatitis C virus entry and glucocorticosteroids

Abstract

Pole Hepato-digestif, Hopitaux Universitaires de Strasbourg, Strasbourg, FranceCOMMENTARY ON:Glucocorticosteroids increase cell entry by hepatitis C virus.Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I,Manns MP, Wedemeyer H, Pietschmann T. Gastroenterology.2010;138:1875–84. Copyright (2010). Abstract reprinted withpermission from Elsevier.http://www.ncbi.nlm.nih.gov/pubmed/20152835Background & Aims:Corticosteroids are used as immunosuppres-sants in patients with autoimmune disorders and transplant recipi-ents. However, these drugs worsen hepatitis C virus (HCV)recurrence after liver transplantation, suggesting that they maydirectly exacerbate HCV infection.Methods:The influence of immunosuppressive drugs on HCV repli-cation, assembly, and entry was assessed in Huh-7.5 cells and pri-mary human hepatocytes using cell culture- and patient-derivedHCV. Replication was quantified by immunofluorescence, luciferaseassays, quantitative reverse-transcriptase polymerase chain reac-tion, or core enzyme-linked immunosorbent assays. Expression ofHCV entry factors was evaluated by cell sorting and immunoblotanalyses.Results:Glucocorticosteroids slightly reduced HCV RNA replicationbut increased efficiency of HCV entry by up to 10-fold. This was inde-pendent of HCV genotype but specific to HCV because vesicular sto-matitis virus glycoprotein-dependent infection was not affected bythese drugs. The increase in HCV entry was accompanied by up-reg-ulation of messenger RNA and protein levels of occludin and thescavenger receptor class B type I – two host cell proteins requiredfor HCV infection;increase of entry by glucocorticosteroids wasablated by RU-486, an inhibitor of glucocorticosteroid signalling.Glucocorticosteroids increased propagation of cell culture-derivedHCV approximately 5- to 10-fold in partially differentiated humanhepatoma cells and increased infection of primary human hepato-cytes by cell culture- and patient-derived HCV.Conclusions:Glucocorticosteroides specifically increase HCV entryby up-regulating the cell entry factors occludin and scavenger recep-tor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due toincreased HCV dissemination. 2010 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.Hepatitis C-associated liver failure is the leading indication forliver transplantation (LT). Hepatitis C virus (HCV) re-infection ofthe liver graft occurs immediately after transplantation with arapid increase in HCV RNA post-transplantation [1]. HCV recur-rence is characterized by accelerated histological progression,with up to 30% of patients developing cirrhosis after five yearsfollowing LT [1]. A prophylactic strategy for prevention of re-infection is lacking and interferon-based antiviral therapies havelimited efficacy and tolerability in LT recipients [2]. Thus, recur-rent liver disease with poor outcome has become an increasingproblem facing hepatologists and transplant surgeons [2].Viral and host factors contribute to HCV re-infection and pro-gression of liver disease. Viral factors include efficiency of entry,replication, and production of progeny virus. Host factors includeimmune responses and graft- or donor-related factors. Advanceddonor age and the use of immunosuppression have been postu-lated as risk factors for more rapid fibrosis following LT [3].Furthermore,theadministrationofhighdosesofglucocorticoster-oids(GCs)appearstobeassociatedwiththeseverityofHCVrecur-rence, increased mortality, and graft loss in LT recipients [3].To better understand the impact of immunosuppressive drugson HCV infection, an elegant study from Thomas Pietschmann’slaboratory investigated the effect of GC, cyclosporin A, tacroli-mus, mycophenolate sodium, basiliximab, evrolimus, and azathi-oprine on the HCV life cycle [4]. To identify virus-druginteractions, Ciesek et al. studied HCV entry, replication, andassembly in permissive Huh-7.5 hepatoma cells and primaryhuman hepatocytes using HCV pseudoparticles and infectiousvirions. Using this approach, Ciesek et al. uncovered that GCsenhance HCV entry and dissemination into hepatocytes. Prednis-olone (starting at 10–50