TLR LIGANDS IN GBV-B

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 GBV-B病毒是与人类丙型肝炎病毒关系最密切的病毒，它会引起 绒猴的肝炎。因此，这是丙型肝炎病毒的一种小型动物替代物。这个模型的使用减少了在丙型肝炎病毒研究中对黑猩猩的使用，因为黑猩猩是除人类之外唯一可以使用的动物。感染丙型肝炎病毒。 在这项研究中，我们将检查一种用于治疗慢性丙型肝炎病毒感染的抗病毒化合物在GBV-B感染的绒猴中的抗病毒特性。该化合物具有免疫调节特性，有望诱导包括干扰素在内的先天免疫反应。该化合物已经在食蟹猴身上进行了安全性和诱导先天免疫反应的测试。在进行临床试验之前，需要在体内测试该化合物在合适的丙型肝炎动物模型的肝脏中抑制病毒复制的能力。该化合物的性质是，预计它对GBV-B和丙型肝炎病毒同样有效。由于慢性感染丙型肝炎病毒的黑猩猩缺乏对干扰素的反应，因此感染丙型肝炎病毒的黑猩猩不适合用来检测这种化合物。这项研究将使用12只绒猴。在PK阶段，动物将被给予单剂量灌胃(6只动物)或口服治疗。血样将在24小时内采集两次。在起效阶段之前，动物将休息30天。在有效阶段，动物将被感染GBV-B，然后每隔一天口服15剂复方，连续30天。将在服药前、服药期间和服药后20周内监测血液中的病毒水平。实验动物分为3组，低剂量组、高剂量组和不给药组。这些动物将被密切监测不良事件，包括完整的血细胞计数和血液化学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. GBV-B virus is the virus most closely related to human hepatitis C virus and it causes hepatitis in marmosets. Thus, this is a small animal surrogate for HCV. The use of this model reduces the use of chimpanzees in HCV studies, since chimpanzees are the only animal other than man that can. be infected with HCV. In this study, we will examine an antiviral compound developed to treat chronic HCV infection for antiviral properties in the GBV-B infected marmoset. The compound has immune modulation properties that are expected to induce an innate immune response including IFN. The compound has been tested for safety and induction of innate immune response in cynomolgus monkeys. Prior to progressing to clinical trials, the compound needs to be tested in vivo for the ability to inhibit viral replication in the liver of a suitable animal model for HCV. The nature of the compound is such that it is expected to be equally effective against GBV-B and HCV. Due to the lack of response to IFN in HCV chronically infected chimpanzees, the HCV infected chimpanzee is not a suitable model for the testing of this compound. The study will use 12 marmosets. In the PK phase, the animals will be given a single oral dose by gavage (6 animals) or with an oral treat. Blood samples will be taken twice over 24 hrs. The animals will be rested for 30 days prior to the efficacy phase. In the efficacy phase, animals will be infected with GBV-B and then given 15 oral doses of compound, every other day for 30 days. The level of virus will be monitored in the blood before, during and after drug administration for a period of 20 weeks. The animals will be divided into 3 groups, low dose, high dose and no drug. The animals will be monitored closely for adverse events including complete blood counts and blood chemistries.