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T-cell therapy for chronic viral hepatitis

Published:August 25, 2017DOI:https://doi.org/10.1016/j.jcyt.2017.07.011

      Abstract

      Although therapy for chronic hepatitis C virus infection has delivered remarkable cure rates, curative therapies for hepatitis B virus (HBV) may only be available in the distant future. The possibility to eliminate or at least stably maintain low levels of HBV replication under the control of a functional anti-host response has stimulated the development of specific immunotherapies for HBV infection. We reviewed the development of T-cell therapy for HBV, highlighting its potential antiviral efficiency but also its potential toxicities in different groups of chronic HBV patients.
      Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the only two communicable diseases in which there have been increases in related morbidity and mortality over the past 20 years [
      • Stanaway J.D.
      • Flaxman A.D.
      • Naghavi M.
      • Fitzmaurice C.
      • Vos T.
      • Abubakar I.
      • et al.
      The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013.
      ]. Both viruses are chronically infecting about 500 million people (HBV ~350 million, HCV ~150 million) and represent the seventh most frequent cause of death worldwide [
      • Stanaway J.D.
      • Flaxman A.D.
      • Naghavi M.
      • Fitzmaurice C.
      • Vos T.
      • Abubakar I.
      • et al.
      The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013.
      ]. HBV and HCV are hepatotropic, non-cytopathic viruses able to establish persistent infections that cause different degrees of hepatic inflammation (chronic hepatitis), leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC).
      The two viruses are unrelated and virologically different. HCV remains prevalent in North America and Europe, whereas chronic hepatitis B is prevalent in Asia and sub-Saharan Africa [
      • Stanaway J.D.
      • Flaxman A.D.
      • Naghavi M.
      • Fitzmaurice C.
      • Vos T.
      • Abubakar I.
      • et al.
      The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013.
      ,
      • Liaw Y.-F.
      • Chu C.-M.
      Hepatitis B virus infection.
      ]. HCV is an RNA virus belonging to the Flaviviridae family, and HBV is a DNA virus of the Hepadnaviridae family and uses reverse transcriptase to synthesize its DNA from a pre-genomic RNA form [
      • Wieland S.F.
      • Chisari F.V.
      Stealth and cunning: hepatitis B and hepatitis C viruses.
      ]. HCV is able to activate in the infected host a classical type I interferon (IFN)-mediated innate response [
      • Wieland S.F.
      • Chisari F.V.
      Stealth and cunning: hepatitis B and hepatitis C viruses.
      ], whereas HBV generally escapes innate immune recognition and does not activate type I IFN-mediated immunity. Chronic HBV and HCV infections are both characterized by quantitative and functional defects of virus-specific T-cell response [
      • Rehermann B.
      • Bertoletti A.
      Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections.
      ,
      • Kurktschiev P.D.
      • Raziorrouh B.
      • Schraut W.
      • Backmund M.
      • Wachtler M.
      • Wendtner C.M.
      • et al.
      Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction.
      ]. The frequency of virus-specific T cells is extremely low, and virus-specific T cells show features of exhaustion in both chronic HBV and HCV patients [
      • Bertoletti A.
      • Ferrari C.
      Adaptive immunity in HBV infection.
      ]. However, the quantitative and functional defects are more pronounced in HBV infections, with T cells virtually undetectable in the blood of many chronic HBV patients by ex vivo analysis [
      • Tan A.T.
      • Loggi E.
      • Boni C.
      • Chia A.
      • Gehring A.J.
      • Sastry K.S.R.
      • et al.
      Host ethnicity and virus genotype shape the hepatitis B virus-specific T-cell repertoire.
      ,
      • Webster G.J.M.
      • Reignat S.
      • Brown D.
      • Ogg G.S.
      • Jones L.
      • Seneviratne S.L.
      • et al.
      Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis b virus proteins in patients with chronic hepatitis B: implications for immunotherapy.
      ,
      • Rehermann B.
      • Fowler P.
      • Sidney J.
      • Person J.
      • Redeker A.
      • Brown M.
      • et al.
      The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.
      ]. In addition, while frequency and impact of viral mutations in T cell epitopes are frequently detectable in HCV infections [
      • Dazert E.
      • Neumann-Haefelin C.
      • Bressanelli S.
      • Fitzmaurice K.
      • Kort J.
      • Timm J.
      • et al.
      Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27–restricted human immune response.
      ], viral mutations affecting CD8 T-cell epitopes are scarcer in chronic HBV patients [
      • Bertoletti A.
      • Ferrari C.
      Adaptive immunity in HBV infection.
      ,
      • Kefalakes H.
      • Budeus B.
      • Walker A.
      • Jochum C.
      • Hilgard G.
      • Heinold A.
      • et al.
      Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure.
      ,
      • Rehermann B.
      • Pasquinelli C.
      • Mosier S.M.
      • Chisari F.V.
      Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection.
      ].
      Of extreme practical importance in relation to the potential impact of T-cell therapy for HBV and HCV are the efficacies of currently available treatments. New therapies for HCV have delivered remarkable cure rates, with more than 90% of patients achieving viral clearance with all oral direct-acting antivirals [
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Bräu N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      ]. In contrast, curative therapies for HBV will not be available until the distant future (14). Thus, although it is difficult to see a possible therapeutic advantage of a new T-cell-based therapy in chronic HCV patients, the fact that current therapies for HBV only partially suppress but do not eliminate HBV from the infected host has encouraged research for new and more radical therapies designed to eliminate or at least stably maintain low levels of HBV replication under the control of a functional anti-host response. For these reasons, in this review, we concentrate on the development of T-cell therapy for HBV. T-cell therapy for HCV chronic infection is certainly important for understanding the mechanisms of T-cell antiviral control [
      • Pasetto A.
      • Frelin L.
      • Aleman S.
      • Holmström F.
      • Brass A.
      • Ahlén G.
      • et al.
      TCR-redirected human T cells inhibit hepatitis C virus replication: hepatotoxic potential is linked to antigen specificity and functional avidity.
      ,
      • Balasiddaiah A.
      • Davanian H.
      • Aleman S.
      • Pasetto A.
      • Frelin L.
      • Sällberg M.
      • et al.
      Hepatitis C virus-specific T cell receptor mRNA-engineered human T cells: impact of antigen-specificity on functional properties.
      ], but their use for therapy appears unlikely.

      Key Words

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