title: Toll-IL1 receptor-mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated-IFN in HBeAg-positive CHB patients.
abstract: Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.
authors.affiliation: Department of Medicine, Monash University (MMC), Melbourne, Vic., Australia.
authors.forename: K
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: Monash Institute of Medical Research, Clayton, Vic., Australia.
authors.forename: T
authors.initials: T
authors.lastname: Lang
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.
authors.forename: K
authors.initials: K
authors.lastname: Ryan
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.
authors.forename: R
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Monash University (MMC), Melbourne, Vic., Australia.
authors.forename: N A
authors.initials: NA
authors.lastname: Skinner
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.|Department of Gastroenterology, St Vincent's Hospital, Melbourne, Vic., Australia.
authors.forename: A J V
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.|Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: New Zealand Liver Transplant Unit, Auckland, New Zealand.
authors.forename: F
authors.initials: F
authors.lastname: Weilert
authors.affiliation: New Zealand Liver Transplant Unit, Auckland, New Zealand.
authors.forename: W
authors.initials: W
authors.lastname: Abbott
authors.affiliation: New Zealand Liver Transplant Unit, Auckland, New Zealand.
authors.forename: E
authors.initials: E
authors.lastname: Gane
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.
authors.forename: D
authors.initials: D
authors.lastname: Colledge
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Centre, Memphis, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.
authors.forename: S
authors.initials: S
authors.lastname: Locarnini
authors.affiliation: Monash Institute of Medical Research, Clayton, Vic., Australia.
authors.forename: A
authors.initials: A
authors.lastname: Mansell
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic., Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Revill
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000145:classification* / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
keywords: chronic HBV; genotype; innate immunity; interferon; treatment response