免疫调节剂AIC649与恩替卡韦联合治疗在慢性乙型肝炎的土拨

StephenW

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B
Kyle E Korolowicz  1 , Manasa Suresh  1 , Bin Li  1 , Xu Huang  1 , Changsuek Yon  1 , Xuebing Leng  1 , Bhaskar V Kallakury  2 , Robin D Tucker  3 , Stephan Menne  1
Affiliations
Affiliations

    1
    Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA.
    2
    Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA.
    3
    Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC 20057, USA.

    PMID: 33918831 DOI: 10.3390/v13040648

Abstract

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.

Keywords: TLR9; antiviral efficacy; chronic hepatitis B; entecavir; immune response; parapoxvirus; woodchuck.

StephenW

免疫调节剂AIC649与恩替卡韦联合治疗在慢性乙型肝炎的土拨鼠模型中产生抗病毒功效
Kyle E Korolowicz 1，Manasa Suresh 1，Bin Li 1，Xu Huang 1，Changsuek Yon 1，Xuebing Leng 1，Bhaskar V Kallakury 2，Robin D Tucker 3，Stephan Menne 1
隶属关系
隶属关系

    1个
    美国华盛顿哥伦比亚特区乔治敦大学医学中心微生物学和免疫学系。
    2个
    美国华盛顿特区，乔治敦大学医学中心，病理学系，20057。
    3
    美国华盛顿特区，乔治敦大学医学中心，比较医学科。

    PMID：33918831 DOI：10.3390 / v13040648

抽象的

由于当前对慢性乙型肝炎（CHB）的干预很少能治愈，因此需要更有效的药物。用新型免疫调节剂AIC649（一种基于副痘病毒的toll样受体9依赖性和非依赖性途径的刺激物）短期治疗土拨鼠已显示可通过独特的双相反应模式减少病毒DNA和表面抗原。本研究评估了长期AIC649与恩替卡韦联合治疗在土拨鼠中的效力和安全性。 AIC649单次治疗可引起血清病毒DNA以及表面抗原和e抗原的适度降低，这些降低与先前观察到的相同双相反应模式有关。恩替卡韦单药治疗可减少短暂的病毒血症，但不能降低抗原血症，而AIC649 /恩替卡韦联合治疗可控制病毒。在AIC649 /恩替卡韦治疗的土拨鼠中，病毒抗原的不可检测性和抗体的诱导与肝脏中干扰素的表达和病毒复制的抑制有关。联合治疗耐受良好，肝酶升高较小且短暂。结论是，AIC649介导的作用最有可能是基于对CHB缺乏的抗病毒免疫反应的改善和/或重构。作为Entecavir的组合伴侣，AIC649的抗病毒功效显着增强。这项临床前研究支持AIC649在治疗人类CHB方面的未来评估。

关键字：TLR9；抗病毒功效；慢性乙型肝炎恩替卡韦免疫反应;副痘病毒土拨鼠。

newchinabok

审美疲劳了

乙肝人1949

老鼠都不够用了。哈哈哈哈哈哈哈哈哈哈哈哈好哈