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Toll‐ IL 1 receptor‐mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated‐ IFN in HB e A g‐positive CHB patients
Author(s) -
Visvanathan K.,
Lang T.,
Ryan K.,
Wilson R.,
Skinner N. A.,
Thompson A. J. V.,
Ahn S. H.,
Weilert F.,
Abbott W.,
Gane E.,
Colledge D.,
Li K.,
Locarnini S.,
Mansell A.,
Revill P. A.
Publication year - 2016
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12477
Subject(s) - immunology , immune system , seroconversion , hepatitis b virus , innate immune system , toll like receptor , genotype , pegylated interferon , receptor , medicine , biology , virology , virus , chronic hepatitis , gene , ribavirin , biochemistry
Summary Patients with hepatitis B e antigen ( HB e A g)‐positive chronic hepatitis B ( CHB ) have suppressed TLR 2 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 ( P eg‐ IFN ) therapy of HB e A g seroconversion in HB e A g‐positive patients. We showed that as early as 4 weeks after initiation of P eg‐ IFN , future HB e A g seroconverters had significantly elevated levels of TLR 2 expression on monocytes. TLR 2‐associated IL ‐6 production at baseline and week 4 of therapy and TLR 4 IL ‐6 production at week 4 were also markedly elevated in HB e A g 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 HB e A g proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HB e A g‐mediated modulation of TLR signalling was also observed in H uh7 cells, following stimulation with P am3 C ys. Importantly, the addition of IFN ‐α to TLR 2‐stimulated cells cotransfected with an HB e A g expression plasmid reversed HB e A g‐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 HB e A g seroconversion in this setting. Furthermore, our findings suggest there is differential genotype‐specific HB e A g suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.