Intrahepatic transcriptomics reveals gene signatures in chronic hepatitis B patients responded to interferon therapy

Chronic hepatitis B virus (HBV) infection remains a substantial public health burden worldwide. Alpha-interferon (IFNα) is one of the two currently approved therapies for chronic hepatitis B (CHB), to explore the mechanisms underlying IFNα treatment response, we investigated baseline and 24-week on-treatment intrahepatic gene expression profiles in 21 CHB patients by mRNA-seq. The data analyses demonstrated that PegIFNα treatment significantly induced antiviral responses. Responders who achieved HBV DNA loss and HBeAg or HBsAg seroconversion displayed higher fold change and larger number of up-regulated interferon-stimulated genes (ISGs). Interestingly, lower expression levels of certain ISGs were observed in responders in their baseline biopsy samples. In HBeAg+ patients, non-responders had relative higher baseline HBeAg levels than responders. More importantly, HBeAg− patients showed higher HBsAg loss rate than HBeAg+ patients. Although a greater fold change of ISGs was observed in HBeAg− patients than HBeAg+ patients, upregulation of ISGs in HBeAg+ responders exceeded HBeAg− responders. Notably, PegIFNα treatment increased monocyte and mast cell infiltration, but decreased CD8 T cell and M1 macrophage infiltration in both responders and non-responders, while B cell infiltration was increased only in responders. Moreover, co-expression analysis identified ribosomal proteins as critical players in antiviral response. The data also indicate that IFNα may influence the production of viral antigens associated with endoplasmic reticulum. Collectively, the intrahepatic transcriptome analyses in this study enriched our understanding of IFN-mediated antiviral effects in CHB patients and provided novel insights into the development of potential strategies to improve IFNα therapy.

慢性乙型肝炎病毒（HBV）感染仍是全球范围内不容忽视的重大公共卫生负担。α干扰素（IFNα）是目前获批用于慢性乙型肝炎（CHB）治疗的两类疗法之一。为探究IFNα治疗应答的潜在机制，本研究通过mRNA测序（mRNA-seq），对21名慢性乙型肝炎患者的基线及治疗24周时的肝内基因表达谱进行了分析。数据分析显示，聚乙二醇化干扰素α（PegIFNα）治疗可显著诱导抗病毒应答。实现HBV DNA转阴及乙型肝炎e抗原（HBeAg）或乙型肝炎表面抗原（HBsAg）血清学转换的应答者，其干扰素刺激基因（ISGs）的上调倍数更高、上调基因数量更多。值得注意的是，应答者的基线肝活检样本中，部分ISGs的表达水平反而更低。在HBeAg阳性患者中，无应答者的基线HBeAg水平相对高于应答者。尤为重要的是，HBeAg阴性患者的HBsAg转阴率高于HBeAg阳性患者。尽管HBeAg阴性患者的ISGs上调倍数高于HBeAg阳性患者，但HBeAg阳性应答者的ISGs上调幅度仍超过HBeAg阴性应答者。值得关注的是，无论应答者还是无应答者，聚乙二醇化干扰素α治疗均会增加单核细胞与肥大细胞的肝内浸润，却减少CD8阳性T细胞及M1型巨噬细胞的浸润；而B细胞浸润仅在应答者中出现升高。此外，共表达分析鉴定发现，核糖体蛋白是抗病毒应答过程中的关键作用分子。本研究数据还表明，IFNα或可影响与内质网相关的病毒抗原生成。综上，本研究通过肝内转录组分析，深化了我们对慢性乙型肝炎患者IFN介导的抗病毒作用的认知，并为优化IFNα治疗的潜在策略开发提供了全新视角。