Restoration of pathways implicated in T cell exhaustion following HCV infection.

据估计，全世界有2亿人感染丙型肝炎病毒（HCV），其中约1.7亿人是慢性携带者，包括25万英国人口。HCV感染可导致慢性肝损伤、肝硬化和肝癌：目前没有广泛有效的治疗方法，也没有疫苗。人们普遍认为，如果要自然清除病毒，就需要受感染个体产生有效的免疫应答。这种反应的主要成分是通过T细胞产生的。更好地理解这种免疫反应及其失败的原因，对于开发有效的HCV抗病毒药物至关重要。研究病毒生命周期及其干扰方面的体外复制系统的开发极大地帮助了该领域，然而，合适的小动物模型的可用性阻碍了HCV抗病毒药的发现和开发。由于HCV仅可靠地感染人和黑猩猩，因此经常使用替代模型，即绢毛猴的GB病毒B（GBV-B）感染。GBV-B与HCV高度相似：它是嗜肝的，其基因组结构和疾病发病机制与HCV密切相似。与失败的T细胞免疫应答相关的特定途径已被确认在HCV感染的man. This失败所带来的T细胞表面上的特定蛋白质的上调，导致一个？筋疲力尽？表型最近的研究表明，用特异性抗体阻断上调的蛋白质可能部分恢复T细胞的正常功能。这突出了治疗干预的潜力。这项工作计划是为了确认的身份GBV-B感染中的T细胞耗竭途径在绢毛猴模型。使用T细胞分离的绢毛猴，我们将努力重建的功能？筋疲力尽？体外使用特异性抗体混合物的T细胞。这项研究的成功将使我们能够考虑进一步申请资金，以证明动物模型中正常T细胞功能的恢复。这将建立GBV-B/tamarin模型作为一个合适的临床前平台，我们可以评估这些免疫调节抗体作为HCV抗病毒药物的有效性。

Of the estimated 200 million individuals worldwide infected with hepatitis C virus (HCV), approximately 170 million people are chronic carriers, including 250,000 of the UK population. HCV infection can lead to chronic liver damage, cirrhosis and liver cancer: there is currently no broadly effective treatment and no vaccine. It is accepted that an effective immune response by the infected individual is required if the virus is to be cleared naturally. A major component of this response is generated through T cells. A greater understanding of this immune response, and the reasons for its failure, is central to developing effective antivirals for HCV. Development of in vitro replication systems to investigate aspects of viral lifecycle and interference thereof, has aided the field greatly, however, the availability of a suitable small animal model has hindered the discovery and development of antivirals for HCV. Since HCV only reliably infected man and chimpanzees, a surrogate model, the GB virus, B (GBV-B) infection of tamarins, is often used. GBV-B is highly similar to HCV: it is hepatotropic and its genome organisation and disease pathogenesis closely parallel that of HCV. Specific pathways associated with a failed T cell immune response have been recognised in HCV infection in man. This failure is brought about by up-regulation of specific proteins on the surface of T cells, leading to an ?exhausted? phenotype. Recent studies have indicated that blocking the up-regulated proteins with specific antibodies may partially restore the normal function of the T cells. This highlights the potential for therapeutic intervention.This programme of work is to confirm the identity of the T cell exhaustion pathways in GBV-B infection in the tamarin model. Using T cells isolated from the tamarins we will endeavour to reconstitute the function of the ?exhausted? T cells using cocktails of specific antibodies in vitro. Success with this study will enable us to consider a further application for funding to demonstrate the restoration of the normal T cell function in the animal model. This will establish the GBV-B/tamarin model as a suitable preclinical platform from which we can evaluate the effectiveness of these immune modulatory antibodies as antivirals for HCV.