HCV/GBV-B嵌合病毒感染狨猴早期诱导的细胞免疫抑制作用对慢性感染转归的影响

GB virus B (GBV-B) is a hepacivirus of flaviviridae phylogenetically close to hepatitis C virus (HCV), which is able to infect marmosets and mostly presents in the status of spontaneous viral clearance or resolved infection outcome. In our previous studies (Li T et al. Hepatology 2014; Zhu S et al. J Virol 2016), we established HCV whole structural proteins CE1E2p7/GBV-B and major non-structural proteins NS2-4A/GBV-B chimeric viruses infected marmoset models, which appear to persistent viremia, typical pathological changes and specific immune response of viral hepatitis, and mostly present chronic infection outcome. Why do HCV/GBV-B or GBV-B infected marmosets develop into two different statuses of infection outcomes? We hypothesize that the chronic outcome of viral infection may be dependent on specific cellular immune suppression by activation of immune regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSCs) induced by viral antigens in the early phase of infected marmosets. Could this chronic outcome of HCV/GBV-B infection in marmosets be reversed through intervention of immune regulation? In this proposal, basing on the viruses infected marmosets, the proposed study will deeply analyze the viral evolution and molecular cellular immune response at the early phase from initial infection of marmosets. Furthermore, the study will investigate the molecular mechanism of immune regulation and intervention impacting on the outcome of virus clearance or persistence from the virus infected marmosets. The data obtained from the proposed study will provide critically theoretic support for prevention and treatment of HCV and other viral chronic infections in humans.

GB病毒B（GBV-B）与丙型肝炎病毒（HCV）同属黄病毒科肝病毒属，前者能够感染狨猴，多以自然康复转归。前期我们建立了HCV完整结构蛋白CE1E2p7/GBV-B和HCV主要非结构蛋白NS2-4A/GBV-B嵌合病毒感染狨猴模型，呈现持续病毒血症、典型病毒性肝炎病理变化和免疫反应特征，多以慢性感染转归。为什么HCV/GBV-B与GBV-B感染狨猴呈现不同的转归状态？本课题认为嵌合病毒感染狨猴慢性转归，可能是在感染早期（10周内），HCV抗原诱导宿主特异性细胞免疫抑制作用所致。这种慢性感染转归能否通过免疫调节干预而逆转呢？针对前面两个问题，本课题拟以建立的HCV/GBV-B嵌合病毒感染狨猴为研究对象，以GBV-B感染狨猴为对照，揭示病毒侵入机体早期进化和宿主分子细胞免疫状态，探究分子免疫调节与干预对病毒感染慢性转归的影响和作用机制，为HCV及其它病毒慢性感染的免疫防治提重要供理论依据。

基于HCV/GBV-B与GBV-B感染狨猴呈现不同的转归状态，本课题以HCV/GBV-B嵌合病毒感染狨猴为研究对象，以GBV-B感染狨猴为对照，利用两种狨猴感染模型的差异，证实了抑制性T细胞（Treg）在HCV感染进程中的重要作用，其直接影响了急性感染期后的转归。研究发现HCV/GBV-B嵌合病毒感染狨猴慢性转归，可能是在感染早期（10周内），HCV抗原诱导宿主特异性细胞免疫抑制作用所致。HCV嵌合病毒感染狨猴后，免疫调节细胞（Treg）细胞比例快速上调并维持在较高水平，而病毒特异性效应T细胞反应呈现延迟且峰值较低。HCV结构蛋白可大幅上调感染狨猴PBMCs中的Treg细胞比例。揭示了病毒侵入机体早期进化和宿主分子细胞免疫状态，探究分子免疫调节与干预对病毒感染慢性转归的影响和作用机制，为HCV及其它病毒慢性感染的免疫防治提重要供理论依据。