Abstract
The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.
Highlights
Hepatitis B virus (HBV) infection is an important disease worldwide[1,2]
Our data showed that immune-related genes were the major genes up-regulated in BRB, such as genes encoding important transcription factors or signal transduction molecules for immune response, CD markers, inflammatory chemokines or chemokine receptors, and human leukocyte antigens (HLA), (Figs 1A and S2)
Our results revealed that immune-related genes and pathways are the dominant host responses to chronic active HBV infection and the major determinants of response to IFNαtherapy
Summary
Hepatitis B virus (HBV) infection is an important disease worldwide[1,2]. Current therapy for chronic hepatitis B (CHB) relies upon interferon (IFN)-based therapy or nucleos(t)ide analogues[1]. We aimed to identify the gene expression profiles associated with necroinflammatory activity and the profiles potentially predictive of response to IFN therapy for CHB, as these host factors may shed light on the mechanisms of poor response and on the discovery of target molecules or genes for future drug development. Taking advantage of this treatment cohort, we investigated the paired pre-treatment and post-treatment liver gene expression profiles associated with CHB-related necroinflammatory activities in the IFN responders
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