1、Natural History of HCV infectionExposureSelf Resolution15%Chronic InfectionLiver CirrhosisEnd Stage Liver DiseaseLiver TransplantHepatocellular CarcinomaDeath85%Stable80% (68%) 20% (17%)25% (4%)Slowly Progressive75% (13%)20-30 yrAlcohol HIVHBVImmunosuppressionOlder ageB cellCD8+CTL Hepatocyte CD4+Th
2、 cellYYYYYNKNKTcellsImmune response to HCV infection :Role largely unknown- early, vigorous, multi-specific response- strong NS3-response in resolving acute HCV- TH1 in recovery- TH2 in chronic- vigorous, multi-specific response- CTL exert some control on viral loadantibodies to most structural and
3、non-structural viral proteins are madeBiological Activities of IFNSignalISGIFN-inducedproteinInhibition ofviral replicationInhibition of Cell GrowthRegulation ofCell differentiationActivation of Immune SystemIFN非特异型抗病毒功能IFNReceptor2-5OASRNARnase LSingle-Strand RNAs降解M x proteinvirus多聚酶抑制PKRprotein s
4、ynthesisi抑制IFN immunomodulatory effects增加 MHC I激活 M NK CTL cells诱导 Th 1 cells减少 Th 2 cells抑制 IL-1、 8、 10和 TNF 抗炎IFNProtein Kinase PKRinactiveInitiation FactoreIF-2aPhosphorylatedInitiation FactoreIF-2a PPhosphatase(soluble)PimRNA translation inhibitionProtein Kinase PKRactivedsRNAssRNAReduced capaci
5、ty of mature DC from HCV patients to induce allogeneic T cell proliferation.Bain et al. Gastroenterology 120:51-524, 2001Antagonism of IFN by HCV proteinsIFNProtein Kinase PKRinactiveInitiation FactoreIF-2aPhosphorylatedInitiation FactoreIF-2a PPhosphatase(soluble)PimRNA translation inhibitionProtein Kinase PKRactivedsRNAssRNAHCV E2 HCV NS5A影响 IFN抗 HCV治疗的因素 性别 年龄 种族 体重 感染 HCV时间 细胞免疫状态、 肝脏纤维化程度、脂肪变程度、胰岛素抵抗 HCV基因型、准种、 病毒含量 ISDR变异、 E2胞膜蛋白与 eIF-2a的同源性 病毒下降的速度 以前是否治疗 治疗药物、剂量、给药方法 、联合用药
