TLR LIGANDS IN GBV-B

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 GBV-B病毒是与人类丙型肝炎病毒最密切相关的病毒， 绒猴肝炎因此，这是HCV的小动物替代物。这种模型的使用减少了在HCV研究中使用黑猩猩，因为黑猩猩是除人类之外唯一可以使用的动物。感染HCV。 在这项研究中，我们将研究开发用于治疗慢性HCV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，预期可诱导包括IFN在内的先天性免疫应答。已在食蟹猴中测试了该化合物的安全性和先天免疫应答的诱导。在进行临床试验之前，需要在体内测试该化合物抑制HCV合适动物模型肝脏中病毒复制的能力。该化合物的性质使得预期其对GBV-B和HCV同样有效。由于HCV慢性感染的黑猩猩对IFN缺乏应答，HCV感染的黑猩猩不是测试该化合物的合适模型。该研究将使用12只绒猴。在PK阶段，将通过灌胃（6只动物）或经口给药对动物进行单次经口给药。将在24小时内采集两次血样。在有效性阶段前，动物将休息30天。在效力阶段，将用GBV-B感染动物，然后每隔一天给予15个口服剂量的化合物，持续30天。将在给药前、给药期间和给药后监测血液中的病毒水平，持续20周。将动物分为3组，低剂量组、高剂量组和无药物组。将密切监测动物的不良事件，包括全血细胞计数和血生化。

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.