人类免疫缺陷病毒与丙型肝炎病毒共感染加剧丙肝病程进展的机制研究

Hepatitis C virus (HCV) coinfection in human immune deficiency virus (HIV)-1-positive individuals is common and which can accelerate the progression to fibrosis, end-stage liver disease, and death. The mechanisms of accelerated liver fibrosis in HIV/HCV coinfection are not well understood. Our pilot study showed that HCV specific CTL play a very important role in the clearance of HCV and successful response to ART, while HIV coinfection induced impairment of CD8 function, which result in a insufficient HCV specific CTL response. According to these data, we put forward to our hypotheses, HIV accelerate the progression to fibrosis in HIV/HCV co-infected patients by impairment of CTL function. To address this issue, an unique cohort was found, in which all candidates were infected with a narrow stain of HIV/HCV at the same time; in addition, several technologies in cellular immunity, such as, enzyme-linked immunospot assay (ELISpot), Tetramer staining, CTL clone, and sequence analysis methods were employed to identify HCV specific immunodominant epitope, to clarify the diversity in differentiation, proliferation, apoptosis, exhaust of HCV specific CTL, to explore the distinction in HCV mutation under HCV specific CTL driving pressure, between HIV/HCV co-infection and mono HCV infection. We expect to explain the underlying mechanism through three levels, epitope, CTL, and interaction between HCV and host, to explore the role of HIV co-infection to the impairment of HCV specific CTL and to the accelerated progression of liver diseases.The study of interaction amongst HIV, HCV and host immunity will enhance our understanding in HIV/HCV co-infection, promote the development of clinical evaluation, and provide new target in the immunologic intervention.

人类免疫缺陷病毒（HIV）与丙肝病毒（HCV）共感染加速丙肝病程进展但机制尚不明确。前期发现HCV特异性细胞毒性T细胞（CTL）在HCV自然清除和抗病毒中发挥重要作用；与单独HCV感染相比，HIV/HCV共感染者HCV特异性CTL数量未减少但功能受损。因此提出假设：HIV通过影响HCV特异性CTL反应能力，导致HIV/HCV共感染肝病进展加剧。为验证假设，课题组以感染时间/方式一致，感染病毒同源的有偿献血人员（HIV/HCV共感染和单独HCV感染）为研究队列；运用ELISpot、Tetramer、细胞克隆及序列比对技术，筛选免疫优势抗原表位、明确其病毒序列变异位点、比较HCV特异性CTL功能异同、探讨HCV特异性CTL克隆与抗原表位（初始/变异位点）亲和力差异。探索HIV影响HCV特异性CTL反应能力的作用路径，阐述HIV、HCV及宿主免疫相互影响机制、寻找病情愈后评估及免疫干预新靶点。

人类免疫缺陷病毒（HIV）与丙肝病毒（HCV）共感染加速丙肝病程进展但机制尚不明确。前期发现HCV 特异性细胞毒性T细胞（CTL）在HCV自然清除和抗病毒中发挥重要作用；与单独HCV感染相比，HIV/HCV 共感染者HCV特异性CTL数量未减少但功能受损。因此提出假设：HIV通过影响HCV特异性CTL反应能力，导致HIV/HCV共感染肝病进展加剧。为验证假设，课题组以感染时间/方式一致，感染病毒同源的有偿献血人员（HIV/HCV共感染和单独HCV感染）为研究队列；运用ELISpot、Tetramer、细胞克隆及序列比对技术，筛选免疫优势抗原表位、明确其病毒序列变异位点、比较HCV特异性CTL功能异同、探讨HCV特异性CTL克隆与抗原表位（初始/变异位点）亲和力差异。探索HIV影响HCV特异性CTL反应能力的作用路径，阐述HIV、HCV及宿主免疫相互影响机制、寻找病情愈后评估及免疫干预新靶点。.本项目研究发现，共感染患者中HCV慢性化率明显高于单独HCV感染者，并且HCV病毒载量明显高于单独HCV感染者。提示：共感染影响HCV病毒清除和HCV病毒复制。共感染患者中纤维化指数明显高于单独HCV感染者，并且谷丙转氨酶明显高于单独HCV感染者。提示：共感染加速慢性丙型肝炎纤维化进展和炎症活动。由此可见，HIV/HCV共感染加速丙肝病情进展。而HIV感染降低共感染HCV特异性T细胞反应数量及反应频率，并且HCV-NS3特异性T细胞反应者肝脏纤维化指数低于无反应者，并且 HCV-NS3特异性T细胞反应高者HCV病毒载量低于反应低者。提示：HCV-NS3的特异性T细胞反应遏制肝纤维化进展和HCV病毒复制 。HIV感染通过影响HCV-NS3特异性CD4+T细胞反应，进而影响HCV病毒复制。HIV影响共感染者CTL细胞分化状态及Treg细胞，进而影响HCV病毒复制及肝脏纤维化进展。因此，HIV通过影响HCV特异性T细胞反应及功能，进而加剧HCV/HCV共感染者丙肝病程进展。