Fletcher Simon P, Chin Daniel J, Gruenbaum Lore, Bitter Hans, Rasmussen Erik, Ravindran Palanikumar, Swinney David C, Birzele Fabian, Schmucki Roland, Lorenz Stefan H, Kopetzki Erhard, Carter Jade, Triyatni Miriam, Thampi Linta M, Yang Junming, AlDeghaither Dalal, Murreddu Marta G, Cote Paul, Menne Stephan
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Roche Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
PLoS Pathog. 2015 Sep 9;11(9):e1005103. doi: 10.1371/journal.ppat.1005103. eCollection 2015 Sep.
Recombinant interferon-alpha (IFN-α) is an approved therapy for chronic hepatitis B (CHB), but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV) infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with recombinant woodchuck IFN-α (wIFN-α) or placebo (n = 12/group) for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8-12/group) at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs) by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB.
重组干扰素-α(IFN-α)是一种已获批准用于治疗慢性乙型肝炎(CHB)的药物,但治疗反应的分子基础仍有待确定。慢性乙型肝炎病毒(HBV)感染的土拨鼠模型具有人类疾病的许多特征,并已被广泛用于评估抗病毒治疗药物。在本研究中,将慢性感染土拨鼠肝炎病毒(WHV)的土拨鼠分为两组,每组12只,分别用重组土拨鼠IFN-α(wIFN-α)或安慰剂治疗15周。wIFN-α治疗可使一部分动物血清和肝脏中的病毒标志物显著降低,停药后通常会观察到病毒反弹。为了确定对wIFN-α抗病毒反应的肝内细胞和分子特征,我们对研究期间不同时间采集的动物肝脏活检样本(每组8 - 12只)的转录谱进行了表征。出乎意料的是,这表明治疗后的抗病毒反应与wIFN-α诱导的大多数干扰素刺激基因(ISG)在肝内的表达无关。相反,治疗反应与肝脏中NK/T细胞特征的诱导、肝内IFN-γ转录反应以及肝损伤生物标志物的升高有关。总体而言,这些数据表明NK/T细胞溶解和非溶解机制介导了对wIFN-α治疗的抗病毒反应。总之,通过在具有完全免疫活性的CHB动物模型中研究重组IFN-α,我们确定这种多效性细胞因子的免疫调节作用而非直接抗病毒活性与治疗反应最密切相关。这对合理设计治疗CHB的新疗法具有重要意义。