以宿主细胞蛋白为靶点的抗病毒药物研究的理论与实践
摘要
病毒感染性疾病严重危害人类健康,以不同病毒酶蛋白为靶点的抑制剂联合治疗方案在临床抗病毒治疗中虽然能取得较好的治疗效果,但是长期用药后病毒易发生耐药性突变,对治疗效果造成严重影响。因此,寻找新的治疗策略是当下抗病毒药物研究工作的重点之一。
随着病毒学研究的深入,发现病毒在复制过程中,会与多种宿主细胞蛋白发生相互作用,一方面,病毒利用特定的宿主细胞蛋白,以促进其复制,另一方面,人体的固有免疫机制通过部分特定功能蛋白在病毒生活周期的不同阶段以多种有效机制抑制病毒复制(这种蛋白称之为细胞限制因子)。因此,寻找与病毒复制相关,而宿主细胞生存非必需的蛋白有可能成为抗病毒药物的新靶点。
第一部分：以往的研究显示,宿主细胞的分子伴侣热应激蛋白Heat stress cognate 70 (Hsc70,HspA8)广泛参与多种RNA和DNA病毒的复制。近期研究表明,Hsc70被包装进入丙型肝炎病毒(Hepatitis C Virus, HCV)病毒颗粒,可调节病毒感染性,并在子代病毒感染过程中帮助HCV RNA的释放。我们认为或许可以以Hsc70为靶点,探索抗HCV病毒新的治疗策略。
我们首先建立在人肝Huh7.5细胞内用实时荧光定量RT-PCR技术检测胞内Hsc70 mRNA表达的药物筛选模型,通过筛选发现本研究所化学合成室合成的化合物IMB-DM122可以特异性地显著下调Hsc70 mRNA水平超过80%,因此我们将IMB-DM122确定为本实验的目标化合物。随后研究发现,IMB-DM122主要是在转录后水平通过降低：mRNA的稳定性来下调Hsc70的表达,能使Hsc70 mRNA T1/2的缩短超过78%。为了研究IMB-DM122在Hsc70 mRNA上的具体作用位点,我们将Hsc70 5'UTR及3'UTR全长分别插入到pLuc中Luc报告基因的上下游的5’端和3’端形成重组质粒,将这些质粒瞬时转染细胞后,用IMB-DM122处理,再分析含有Hsc70 3'UTR及5'UTR的Luc mRNA水平。结果显示插入3’UTR后Luc mRNA的基础表达水平下降68%,而连接5'UTR和野生型pLuc的Luc mRNA的表达水平几乎没有变化。
我们通过含有HCV全长cDNA的质粒pFL-J6/JFH/JC1和Huh7.5肝细胞建立了抗HCV活病毒化合物筛选的模型,并通过该模型发现经IMB-DM122处理后的细胞,无论在mRNA水平,还是在蛋白水平,在Hsc70表达水平下调的同时,HCV也有显著下降。在转染过表达Hsc70的细胞中,相比于对照组,经IMB-DM122处理后,得到更为显著的抗HCV效果,HCV表达水平下降至未处理水平的1／16。上述结果提示,IMB-DM122的抗HCV作用是通过下调胞内Hsc70水平起作用的。进一步通过纯化病毒颗粒并分析后发现,经IMB-DM122处理后的受感染细胞所产的包装在病毒颗粒中的Hsc70含量有显著的下降,所产生的子代病毒的感染力也显著降低。这不仅验证了以往的研究结果,更重要的是开创了用化学方法在细胞内通过下调Hsc70达到抑制HCV复制的研究策略。为了评价药物作用的安全性,我们在细胞毒性实验中发现,IMB-DM122在体外对细胞毒性低；在小鼠体内实验中,腹腔注射浓度高达1000mg/kg也未见任何生长异常,给药后的血液样本中,各项肝肾功能指标也未见异常。
IMB-DM122通过宿主蛋白Hsc70的下调来降低HCV颗粒的感染性,达到良好的抑制病毒复制的效果,并具有较少副作用和降低病毒发生耐药性突变的优势,该作用机制与IFN为核心的治疗策略和其他各种以病毒酶为靶点的病毒抑制剂完全不同,因此我们认为,下调Hsc70表达可能成为新的抗HCV病毒药物的机制。
第二部分：人类载脂蛋白B mRNA编辑酶催化多肽样蛋白3G (human apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G protein, hA3G)属于细胞限制因子,具有一定的组织分布特异性,仅在“非允许性”细胞中表达。hA3G通过特定的包装机制在HIV-1复制过程中选择性包装进入病毒毒粒。在HIV-1的逆转录过程中,hA3G主要通过催化病毒负链cDNA中的dC脱氨为dU,在病毒基因组中引入广泛的超突变从而发挥抗病毒作用。但是HIV-1编码的Vif蛋白可以通过泛素—蛋白酶体的降解途径来拮抗APOBEC3G的抗病毒活性。本文将分别从hA3G的包装机制,hA3G在不同HIV-1宿主细胞中的表达水平,以及筛选小分子化合物抑制Vif介导的hA3G降解三个方向做探索性研究,并探讨其作为潜在抗HIV-1药物靶点的可能性。
我们构建不同长度的hA3G截短质粒,分别单独包含了氨基端CDA区,锌指结构域的连接区(第104-156位氨基酸),羧基端CDA区。构建的质粒与HIV-1 Gag共转染细胞后,分别检测病毒颗粒和胞内蛋白表达,发现只有含第104-156位氨基酸的截短蛋白可以正常包装进入Gag VLP中,而该段缺失的截短蛋白,不能或只有少量包装进入Gag VLP中,该结果表明hA3G第104-156位氨基酸是hA3G包装进入病毒颗粒所必需的。
通过实时荧光定量PCR相对定量检测实验室常用的HIV-1相关细胞系中内源性hA3G mRNA的表达水平,发现HIV-1宿主细胞H9、CEM、MT4都有不同水平的hA3G表达,而人肾上皮细胞293T中hA3G表达水平极低,hA3G表达水平在四种细胞中的高低顺序为：H9>CEM>MT4>293T。该结果表明人体固有免疫机制与HIV病毒的长期斗争与进化中,使hA3G的表达具有倾向于病毒易感细胞的组织分布特异性。后续实验中,我们将利用该细胞模型分析化合物的抗HIV-1活性是否通过hA3G机制。
通过构建抑制Vif介导的hA3G降解的化合物筛选模型,我们从本研究所化合物库中成功筛选到活性化合物IMB-26／35,并通过Cul5 E3连接酶体系确定IMB-26／35是特异性的拮抗Vif对hA3G的降解,而非作用于蛋白酶体通路。我们将IMB-26／35及其部分衍生物通过表面等离子共振实验分析化合物与hA3G或Vif的体外结合活性和主要结合靶点。结果显示,IMB-26／35及其衍生物可与hA3G直接结合,但不与Vif结合,表明该类化合物通过与hA3G直接结合,抑制了Vif与hA3G相互作用,从而实现对hA3G抗病毒活性的保护。然后,我们利用H9、MT4和SupTl(“非允许性”细胞,低水平表达hA3G)细胞模型,检测化合物IMB-26／35的抗HIV-1活性,发现IMB-26／35的抗HIV-1活性与该三种细胞中hA3G表达水平呈正相关,分别使三种细胞中HIV-1水平下降约97%,85%和20%,验证了细胞模型的可靠性。
然后用IMB-26／35及其衍生物处理经HIV-1感染的MT4细胞,检测其抗病毒活性与细胞毒性。结果显示,化合物363、2611、2613、2621等都具有较好的抗病毒效果,而351具有更低的细胞毒性。随后在小鼠体内急毒实验中,未见药物处理的小鼠死亡和显著体重改变,肝肾功能指标未见异常,并且主要器官组织均未见指标组化异常,表明化合物IMB-26以hA3G/Vif为靶点的抗HIV-1作用机制不会影响主要器官的生理功能,是相对安全可靠的。
综上所述,我们的研究从分子水平到细胞水平,再到体内动物毒性实验,不仅旨在对细胞宿主蛋白为靶点的新的抗病毒机制进行理论研究,而且对新机制成为潜在抗病毒治疗方案的可能性进行探索性实践分析。综合上述两部分实验结果,我们认为该新机制具有较好的抗病毒活性,对宿主相对安全的特点,因此,与现有的病毒抑制剂联合应用可能会帮助解决病毒耐药性问题的出现。
Targeting viral enzymes is an effective approach leading to potent drugs; however, newly discovered antiviral agents that act at different binding sites on the enzymes or different viral proteins generate new drug-resistant mutations. It has become very crucial to identify novel drug targets for the control of drug-resistance. This study explored the possibility of using cellular molecules as drug targets to control viral infection. The in vitro investigation has been divided into two parts, for HCV and HIV-1, respectively.
Part I. It has been known that viruses interact with host cellular proteins in their replication cycle, and employ some of them for viral proliferation. Recent study has indicated host Hsc70 protein is packaged into the hepatitis C viral (HCV) particles as a structural component of the virus in the assembly process. It helps HCV RNA releasing into the cytoplasm in the next infection cycle. We investigated whether chemically down-regulating host Hsc70 expression could be a novel strategy to interrupt HCV replication. Using Hsc70 mRNA assay, compounds were screened. IMB-DM122 was found to be an effective and safe inhibitor for Hsc70 mRNA/protein expression in human hepatocytes. IMB-DM122 inhibited HCV replication through destabilizing Hsc70 mRNA, and the T1/2 of host Hsc70 mRNA was reduced by 78% after the compound treatment. The Hsc70 mRNA 3'UTR sequence is the element responsible for IMB-DM122' s effect on Hsc70 mRNA. The compound appears to be highly efficient to the Hsc70-related HCV replication. Treatment of the HCV infected hepatocytes with IMB-DM122 reduced the virion encapsidation of Hsc70, and therefore made a break in HCV replication and infection cycle. IMB-DM122 showed a considerably good safety in vitro as well as in vivo with no indication of harmful effect on liver and kidney functions. It is our conclusion that Hsc70 might be a new drug target and mechanism to inhibit HCV proliferation.
Part II. On the other hand, host innate immunity system fights against viral intruders in a variety of strategies. Human APOBEC3G (hA3G) is part of this system of host cell and has cytidine deaminase activity. It specifically incorporates into the virion during HIV-1 replication. In the HIV-1 reverse transcription process, hA3G deaminates dC to dU in the first minus strand cDNA, and then induce extensive hypermutation in the viral genome. Unfortunately, HIV-1 Vif counteracts the activity of hA3G by an ubiquitin-proteasome-mediated degradation of hA3G, suggesting that the interaction between Vif and hA3G might be a potential target for novel anti-HIV-1 drugs. In this part of work, we first established a screening system to discover compounds that protect hA3G from Vif-mediated degradation. After screening over 8634 samples, two active compounds, IMB-26 and IMB-35, were identified to be blockers for the Vif/hA3G interaction. The compounds specifically inhibited the degradation of hA3G by Vif without interference of the proteasomal function, and efficiently inhibit HIV-1 replication in hA3G-containing cells but not those null of hA3G The anti-HIV activity of IMB-26/35 positively correlated with the endogenous hA3G level in host cells. BIAcore examination found that IMB-26/35 protected hA3G by inhibiting the interaction between Vif and hA3G, and the hA3G protein appeared to be the receptor molecule for binding of the compound. The compounds were safe with a therapeutic index over 200 in vitro. LD50 of IMB-26 in mice was over 1000 mg/kg (ip) with no toxicity in liver and kidney. These data together indicate that Vif/hA3G interaction a new anti-HIV target, and IMB-26/35 potential leads for the discovery of new mechanism anti-HIV drugs.
In summary, host cellular proteins that relate to viral replication could be novel drug targets to inhibit viruses, if their intracellular concentration is not a key factor for cell survival. It might be a potential strategy against drug resistance.
随着病毒学研究的深入,发现病毒在复制过程中,会与多种宿主细胞蛋白发生相互作用,一方面,病毒利用特定的宿主细胞蛋白,以促进其复制,另一方面,人体的固有免疫机制通过部分特定功能蛋白在病毒生活周期的不同阶段以多种有效机制抑制病毒复制(这种蛋白称之为细胞限制因子)。因此,寻找与病毒复制相关,而宿主细胞生存非必需的蛋白有可能成为抗病毒药物的新靶点。
第一部分：以往的研究显示,宿主细胞的分子伴侣热应激蛋白Heat stress cognate 70 (Hsc70,HspA8)广泛参与多种RNA和DNA病毒的复制。近期研究表明,Hsc70被包装进入丙型肝炎病毒(Hepatitis C Virus, HCV)病毒颗粒,可调节病毒感染性,并在子代病毒感染过程中帮助HCV RNA的释放。我们认为或许可以以Hsc70为靶点,探索抗HCV病毒新的治疗策略。
我们首先建立在人肝Huh7.5细胞内用实时荧光定量RT-PCR技术检测胞内Hsc70 mRNA表达的药物筛选模型,通过筛选发现本研究所化学合成室合成的化合物IMB-DM122可以特异性地显著下调Hsc70 mRNA水平超过80%,因此我们将IMB-DM122确定为本实验的目标化合物。随后研究发现,IMB-DM122主要是在转录后水平通过降低：mRNA的稳定性来下调Hsc70的表达,能使Hsc70 mRNA T1/2的缩短超过78%。为了研究IMB-DM122在Hsc70 mRNA上的具体作用位点,我们将Hsc70 5'UTR及3'UTR全长分别插入到pLuc中Luc报告基因的上下游的5’端和3’端形成重组质粒,将这些质粒瞬时转染细胞后,用IMB-DM122处理,再分析含有Hsc70 3'UTR及5'UTR的Luc mRNA水平。结果显示插入3’UTR后Luc mRNA的基础表达水平下降68%,而连接5'UTR和野生型pLuc的Luc mRNA的表达水平几乎没有变化。
我们通过含有HCV全长cDNA的质粒pFL-J6/JFH/JC1和Huh7.5肝细胞建立了抗HCV活病毒化合物筛选的模型,并通过该模型发现经IMB-DM122处理后的细胞,无论在mRNA水平,还是在蛋白水平,在Hsc70表达水平下调的同时,HCV也有显著下降。在转染过表达Hsc70的细胞中,相比于对照组,经IMB-DM122处理后,得到更为显著的抗HCV效果,HCV表达水平下降至未处理水平的1／16。上述结果提示,IMB-DM122的抗HCV作用是通过下调胞内Hsc70水平起作用的。进一步通过纯化病毒颗粒并分析后发现,经IMB-DM122处理后的受感染细胞所产的包装在病毒颗粒中的Hsc70含量有显著的下降,所产生的子代病毒的感染力也显著降低。这不仅验证了以往的研究结果,更重要的是开创了用化学方法在细胞内通过下调Hsc70达到抑制HCV复制的研究策略。为了评价药物作用的安全性,我们在细胞毒性实验中发现,IMB-DM122在体外对细胞毒性低；在小鼠体内实验中,腹腔注射浓度高达1000mg/kg也未见任何生长异常,给药后的血液样本中,各项肝肾功能指标也未见异常。
IMB-DM122通过宿主蛋白Hsc70的下调来降低HCV颗粒的感染性,达到良好的抑制病毒复制的效果,并具有较少副作用和降低病毒发生耐药性突变的优势,该作用机制与IFN为核心的治疗策略和其他各种以病毒酶为靶点的病毒抑制剂完全不同,因此我们认为,下调Hsc70表达可能成为新的抗HCV病毒药物的机制。
第二部分：人类载脂蛋白B mRNA编辑酶催化多肽样蛋白3G (human apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G protein, hA3G)属于细胞限制因子,具有一定的组织分布特异性,仅在“非允许性”细胞中表达。hA3G通过特定的包装机制在HIV-1复制过程中选择性包装进入病毒毒粒。在HIV-1的逆转录过程中,hA3G主要通过催化病毒负链cDNA中的dC脱氨为dU,在病毒基因组中引入广泛的超突变从而发挥抗病毒作用。但是HIV-1编码的Vif蛋白可以通过泛素—蛋白酶体的降解途径来拮抗APOBEC3G的抗病毒活性。本文将分别从hA3G的包装机制,hA3G在不同HIV-1宿主细胞中的表达水平,以及筛选小分子化合物抑制Vif介导的hA3G降解三个方向做探索性研究,并探讨其作为潜在抗HIV-1药物靶点的可能性。
我们构建不同长度的hA3G截短质粒,分别单独包含了氨基端CDA区,锌指结构域的连接区(第104-156位氨基酸),羧基端CDA区。构建的质粒与HIV-1 Gag共转染细胞后,分别检测病毒颗粒和胞内蛋白表达,发现只有含第104-156位氨基酸的截短蛋白可以正常包装进入Gag VLP中,而该段缺失的截短蛋白,不能或只有少量包装进入Gag VLP中,该结果表明hA3G第104-156位氨基酸是hA3G包装进入病毒颗粒所必需的。
通过实时荧光定量PCR相对定量检测实验室常用的HIV-1相关细胞系中内源性hA3G mRNA的表达水平,发现HIV-1宿主细胞H9、CEM、MT4都有不同水平的hA3G表达,而人肾上皮细胞293T中hA3G表达水平极低,hA3G表达水平在四种细胞中的高低顺序为：H9>CEM>MT4>293T。该结果表明人体固有免疫机制与HIV病毒的长期斗争与进化中,使hA3G的表达具有倾向于病毒易感细胞的组织分布特异性。后续实验中,我们将利用该细胞模型分析化合物的抗HIV-1活性是否通过hA3G机制。
通过构建抑制Vif介导的hA3G降解的化合物筛选模型,我们从本研究所化合物库中成功筛选到活性化合物IMB-26／35,并通过Cul5 E3连接酶体系确定IMB-26／35是特异性的拮抗Vif对hA3G的降解,而非作用于蛋白酶体通路。我们将IMB-26／35及其部分衍生物通过表面等离子共振实验分析化合物与hA3G或Vif的体外结合活性和主要结合靶点。结果显示,IMB-26／35及其衍生物可与hA3G直接结合,但不与Vif结合,表明该类化合物通过与hA3G直接结合,抑制了Vif与hA3G相互作用,从而实现对hA3G抗病毒活性的保护。然后,我们利用H9、MT4和SupTl(“非允许性”细胞,低水平表达hA3G)细胞模型,检测化合物IMB-26／35的抗HIV-1活性,发现IMB-26／35的抗HIV-1活性与该三种细胞中hA3G表达水平呈正相关,分别使三种细胞中HIV-1水平下降约97%,85%和20%,验证了细胞模型的可靠性。
然后用IMB-26／35及其衍生物处理经HIV-1感染的MT4细胞,检测其抗病毒活性与细胞毒性。结果显示,化合物363、2611、2613、2621等都具有较好的抗病毒效果,而351具有更低的细胞毒性。随后在小鼠体内急毒实验中,未见药物处理的小鼠死亡和显著体重改变,肝肾功能指标未见异常,并且主要器官组织均未见指标组化异常,表明化合物IMB-26以hA3G/Vif为靶点的抗HIV-1作用机制不会影响主要器官的生理功能,是相对安全可靠的。
综上所述,我们的研究从分子水平到细胞水平,再到体内动物毒性实验,不仅旨在对细胞宿主蛋白为靶点的新的抗病毒机制进行理论研究,而且对新机制成为潜在抗病毒治疗方案的可能性进行探索性实践分析。综合上述两部分实验结果,我们认为该新机制具有较好的抗病毒活性,对宿主相对安全的特点,因此,与现有的病毒抑制剂联合应用可能会帮助解决病毒耐药性问题的出现。
Targeting viral enzymes is an effective approach leading to potent drugs; however, newly discovered antiviral agents that act at different binding sites on the enzymes or different viral proteins generate new drug-resistant mutations. It has become very crucial to identify novel drug targets for the control of drug-resistance. This study explored the possibility of using cellular molecules as drug targets to control viral infection. The in vitro investigation has been divided into two parts, for HCV and HIV-1, respectively.
Part I. It has been known that viruses interact with host cellular proteins in their replication cycle, and employ some of them for viral proliferation. Recent study has indicated host Hsc70 protein is packaged into the hepatitis C viral (HCV) particles as a structural component of the virus in the assembly process. It helps HCV RNA releasing into the cytoplasm in the next infection cycle. We investigated whether chemically down-regulating host Hsc70 expression could be a novel strategy to interrupt HCV replication. Using Hsc70 mRNA assay, compounds were screened. IMB-DM122 was found to be an effective and safe inhibitor for Hsc70 mRNA/protein expression in human hepatocytes. IMB-DM122 inhibited HCV replication through destabilizing Hsc70 mRNA, and the T1/2 of host Hsc70 mRNA was reduced by 78% after the compound treatment. The Hsc70 mRNA 3'UTR sequence is the element responsible for IMB-DM122' s effect on Hsc70 mRNA. The compound appears to be highly efficient to the Hsc70-related HCV replication. Treatment of the HCV infected hepatocytes with IMB-DM122 reduced the virion encapsidation of Hsc70, and therefore made a break in HCV replication and infection cycle. IMB-DM122 showed a considerably good safety in vitro as well as in vivo with no indication of harmful effect on liver and kidney functions. It is our conclusion that Hsc70 might be a new drug target and mechanism to inhibit HCV proliferation.
Part II. On the other hand, host innate immunity system fights against viral intruders in a variety of strategies. Human APOBEC3G (hA3G) is part of this system of host cell and has cytidine deaminase activity. It specifically incorporates into the virion during HIV-1 replication. In the HIV-1 reverse transcription process, hA3G deaminates dC to dU in the first minus strand cDNA, and then induce extensive hypermutation in the viral genome. Unfortunately, HIV-1 Vif counteracts the activity of hA3G by an ubiquitin-proteasome-mediated degradation of hA3G, suggesting that the interaction between Vif and hA3G might be a potential target for novel anti-HIV-1 drugs. In this part of work, we first established a screening system to discover compounds that protect hA3G from Vif-mediated degradation. After screening over 8634 samples, two active compounds, IMB-26 and IMB-35, were identified to be blockers for the Vif/hA3G interaction. The compounds specifically inhibited the degradation of hA3G by Vif without interference of the proteasomal function, and efficiently inhibit HIV-1 replication in hA3G-containing cells but not those null of hA3G The anti-HIV activity of IMB-26/35 positively correlated with the endogenous hA3G level in host cells. BIAcore examination found that IMB-26/35 protected hA3G by inhibiting the interaction between Vif and hA3G, and the hA3G protein appeared to be the receptor molecule for binding of the compound. The compounds were safe with a therapeutic index over 200 in vitro. LD50 of IMB-26 in mice was over 1000 mg/kg (ip) with no toxicity in liver and kidney. These data together indicate that Vif/hA3G interaction a new anti-HIV target, and IMB-26/35 potential leads for the discovery of new mechanism anti-HIV drugs.
In summary, host cellular proteins that relate to viral replication could be novel drug targets to inhibit viruses, if their intracellular concentration is not a key factor for cell survival. It might be a potential strategy against drug resistance.
引文
[1]Szabo E, Lotz G, Paska C, et al. Viral hepatitis:new data on hepatitis C infection. Pathol Oncol Res,2003,9:215-221.
[2]Perz JF, Farrington LA, Pecoraro C, et al. Estimated global prevalence of hepatitis C virus infection.42nd Annual Meeting of the Infectious Diseases Society of America, Boston, MA, USA, Sept 30-Oct 3,2004.
[3]Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol,2006,45:529-538.
[4]Vaccine Research. Hepatitis C.
[5]Robertson B, Myers G, Howard C, et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses:proposals for standardization. International Committee on Virus Taxonomy. Arch Virol,1998,143:2493-2503.
[6]Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science,1989,244:359-362.
[7]Martell M, Esteban JI, Quer J, et al. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes:quasispecies nature of HCV genome distribution. J Virol,1992,66: 3225-3229.
[8]Pawloltsky JM. Hepatitis C virus population dynamics during infection. Curr. Top. Microbiol Immunol,2006,299:261-284.
[9]Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science,1998,282: 938-941.
[10]Levy S, Todd SC, Maecker HT. CD81 (TAPA-1):a molecule involved in signal transduction and cell adhesion in the immune system. Annu. Rev. Immunol,1998,16:89-109.
[11]Petracca R, Falugi F, Galli G, et al. Structure-function analysis of hepatitis C virus envelope-CD81 binding. J. Virol,2000,10:4824-4830.
[12]Scarselli E, Ansuini H, Cerino R, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J,2002,19:5017-5025.
[13]Rhainds D, Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. defining the rules for lipid traders. Int. J. Biochem. Cell Biol,2004,36:39-77.
[14]Yamada E, Montoya M, Schuettler CG, et al. Analysis of the binding of hepatitis C virus genotype la and 1b E2 glycoproteins to peripheral blood mononuclear cell subsets. J. Gen. Virol, 2005,86:2507-2512.
[15]Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science,1996,271:518-520.
[16]Gardner JP, Durso RJ, Arrigale RR, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc. Natl. Acad. Sci. U. S. A,2003,8:4498-4503.
[17]Lozach Y, Lortat-Jacob H, de Lacroix de Lavalette A, et al. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J. Biol. Chem,2003,22:20358-20366.
[18]Cormier EG, Durso RJ, Tsamis F, et al. L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc.Natl. Acad. Sci. U. S. A,2004,39:14067-14072.
[19]Evans MJ, Von Hahn T, Tscherne DM, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature,2007,446:801-805.
[20]Rijnbrand R, Bredenbeek P, Van der Straaten T, et al. Almost the entire 5'non-translated region of hepatitis C virus is required for cap-independent translation. FEBS Lett,1995,365:115-119.
[21]B.J. Yoo BJ, Spaete RR, Geballe AP, et al.5'end-dependent translation initiation of hepatitis C viral RNA and the presence of putative positive and negative translational control elements within the 5'untranslated region. Virology,1992,191:889-899.
[22]Hellen U, Pestova TV. Translation of hepatitis C virus RNA, J. Viral Hepatitis,1999,6:79-87.
[23]Lu HH, Wimmer E. Poliovirus chimeras replicating under the translational control of genetic elements of hepatitis C virus reveal unusual properties of the internal ribosomal entry site of hepatitis C virus, Proc. Natl. Acad. Sci. U. S. A,1996,93:1412-1417.
[24]Reynolds JE, Kaminski A, Kettinen HJ, et al. Unique features of internal initiation of hepatitis C virus RNA translation. EMBO J,1995,23:6010-6020.
[25]Walewski JL, Keller TR, Stump DD, et al. Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame. RNA,2001,7:710-721.
[26]Xu Z, Choi J, Yen TS, et al. Synthesis of a novel hepatitis C virus protein by ribosomal frameshift. EMBO J,2001,20:3840-3848.
[27]Varaklioti A, Vassilaki N, Georgopoulou U, et al. Alternate translation occurs within the core coding region of the hepatitis C viral genome. J. Biol. Chem,2002,277:17713-17721.
[28]Hussy P, Langen H, Mous J, et al. Hepatitis C virus core protein:carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase. Virology,1996,224:93-104.
[29]Weihofen A, Binns K, Lemberg MK, et al. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science,2002,296:2215-2218.
[30]Shi ST, Lee KJ, Aizaki H, et al. Hepatitis C virus RNA replication occurs on a detergent-resistant membrane that cofractionates with caveolin-2. J. Virol,2003,77:4160-4168.
[31]Pfeifer U, Thomssen R, Legler K, et al. Experimental non-A, non-B hepatitis:four types of cytoplasmic alteration in hepatocytes of infected chimpanzees. Virchows Arch., B Cell Pathol. Incl. Mol. Pathol,1980,33:233-243.
[32]Mottola G, Cardinali G, Ceccacci A, et al. Hepatitis C virus nonstructural proteins are localized in a modified endoplasmic reticulum of cells expressing viral subgenomic replicons. Virology,2002, 293:31-43.
[33]Watashi K, Ishii N, Hijikata M, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol. Cell,2005,19:111-122.
[34]Goh PY, Tan YJ, Lim SP, et al. Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. J. Virol, 2004,78:5288-5298.
[35]Hirano M, Kaneko S, Yamashita,HT. et al. Direct interaction between nucleolin and hepatitis C virus NS5B. J. Biol. Chem,2003,278:5109-5115.
[36]Kim S, Seol SK, Song OK, et al. An RNA-binding protein, hnRNP A1, and a scaffold protein, Septin 6, facilitate hepatitis C virus replication, J. Virol,2007,81:3852-3865.
[37]Ali N, Siddiqui A. Interaction of polypyrimidine tract-binding protein with the 5'noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation. J. Virol,1995,69:6367-6375.
[38]Ito T, Lai MM. Determination of the secondary structure of and cellular protein binding to the 3'-untranslated region of the hepatitis C virus RNA genome. J. Virol,1997,71:8698-8706.
[39]Kaito M, Wastanabe S, Tsukiyama-Kohara K, et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J. Gen. Virol,1994,75:1755-1760.
[40]Shimizu YK, Feinstone SM, Kohara M, et al. Hepatitis C virus:detection of intracellular virus particles by electron microscopy. Hepatology,1996,23:205-209.
[41]Serafino A, Valli MB, Andreola F, et al. Suggested role of the Golgi apparatus and endoplasmic reticulum for crucial sites of hepatitis C virus replication in human lymphoblastoid cells infected in vitro. J. Med. Virol,2003,70:31-41.
[42]Sato K, Okamoto H, Aihara S, et al. Demonstration of sugar moiety on the surface of hepatitis C virions recovered from the circulation of infected humans. Virology,1993,196:354-357.
[43]Simmonds P. Viral heterogeneity of the hepatitis C virus. Journal of Hepatology,1999,31:54-60.
[44]Houghton M. Hepatitis C viruses. In:Fields BN, Knipe DM, Howley PM, eds. Fields Virology, 3rd ed. Philadelphia, Lippincott-Raven,1996:1035-1058.
[45]Mondelli MU, Silini E. Clinical significance of hepatitis C virus genotypes. Journal of Hepatology,1999,31:65-70.
[46]US Department of Health and Human Services.Centers for Disease Control and Prevention. Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease. Morbidity and Mortality Weekly Report,1998,47.
[47]World Health Organization. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in Collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. Journal of Viral Hepatology,1999,6:35-47.
[48]National Institutes of Health. Consensus Development Conference Statement:Management of Hepatitis C:2002, June 10-12.2002,
[50]Davis GL, Balart LA., Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon a. A multicenter randomized, controlled trial. Hepatitis. Interventional.Therapy. Group. N. Engl. J. Med,1989,321:1501-1506.
[51]McHutchison JG, Stuart C, Schiff ER, et al. Interferon a-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N. Engl. J. Med,1998,339:1485-1492.
[52]Zeuzem, S. Feinman SV, Rasenack J,. et al. Peginterferon α-2a in patients with chronic hepatitis C. N. Engl. J. Med,2000,343:1666-1672.
[53]Zic, I. Peginterferon a/ribavirin combination therapy for the treatment of hepatitis C infection. Gastroenterol. Nurs,2005,28:317-328.
[54]Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon a-2b to interferon a-2b as initial treatment for chronic hepatitis C. Hepatology 34, 395-403(2001).
[55]Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon a-2b plus ribavirin compared with interferon a-2b plus ribavirin for initial treatment of chronic hepatitis C:a randomised trial. Lancet, 2001,358:958-965.
[56]Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon a-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med.347,975-982 (2002).
[57]Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C:efficacy, side effects, and complications. Gut,2006,55:1350-1359.
[58]Balan V, Nelson DR, Sulkowski MS, et al. A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-a fusion protein in chronic hepatitis C patients who have failed previous interferon-α-based therapy. Antivir. Ther,2006,11:35-45.
[59]Zeuzem S, Yoshida EM, Benhamou Y, et al. Sustained virologic response rates with albinterferon α-2b plus ribavirin treatment in IFN-naive, chronic hepatitis C genotype I patients. Hepatology,2007, 46(Suppl.1),317A.
[60]Robert GG. Treating HCV with ribavirin analogues and ribavirin-like molecules. Journal of Antimicrobial Chemotherapy,2006,57:8-13.
[61]Benhamou Y, Pockros P, Rodrieuez TM, et al. The safety and efficacy of viramidine(?) plus pegylated interferon α-2b versus ribavirin plus pegylated interferon α-2b in therapynaive patients infected with HCV:Phase 3 results. J. Hepatol,2006,44 (Suppl.2), S273.
[62]Marcellin P, Lurie Y, Rodrigues TM, et al. The safety and efficacy of taribavirin plus pegylated interferon α-2a versus ribavirin plus pegylated interferon α-2a in therapy-naive patients infected with HCV:Phase 3 results. J. Hepatol,2007,46 (Suppl.1), S7.
[63]Paulsen RB, Seth PP, Swayze EE, et al. Inhibitor-induced structural change in the HCV IRES domain Ⅱa RNA. Proc Natl Acad Sci U S A,2010,107:7263-7268.
[64]Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature,2003,426:186-189.
[65 Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol,2009,6:403-411.
[66]Mederacke I, Wedemeyer H, Manns MP. Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. Curr Opin Investig Drugs,2009,10:181-189.
[67]Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med,2009,360:1839-1850.
[68]McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med,2009,360:1827-1838.
[69]Olsen DB, Carroll SS, Handt L, et al. HCV antiviral activity and resistance analysis in chronically infected chimpanzees treated with NS3/4A protease and NS5B polymerase inhibitors. J. Hepatol,2007,46 (Suppl.1), S298.
[70]Roberts S, Cooksley G, Shaw D, et al. Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV patients. J. Hepatol, 2006,44 (Suppl.2), S269.
[71]Afdhal N, Brien CO, Godofsky E, et al. Valopicitabine (NM283), alone or with peg-interferon, compared to peg-interferon/ribavirin (pegIFN/RBV) retreatment in hepatitis C patients with prior non-response to pegIFN/RBV:week 24 results. J. Hepatol.44 (Suppl.2), S19(2006).
[72]Dieterich D, Lawitz E, Nguyen T, et al. Early clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection:first results from a Phase Ⅱb trial. J. Hepatol,2006,44 (Suppl.2), S271.
[73]Kandil S, Biondaro S, Vlachakis D, et al. Discovery of a novel HCV helicase inhibitor by a de novo drug design approach. Bioorg Med Chem Lett,2009,19::2935-2937.
[74]Luscombe CA, Huang ZH, Murray MG, et al. A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-a-2b and nucleoside analogues. Antiviral Research,2010,86:144-153.
[75]McHutchison JG, Bartenschlager R, Patel K, et al. The face of future hepatitis C antiviral drug development:recent biological and virologic advances and their translation to drug development and clinical practice. J. Hepatol,2006,44:411-421.
[76]Paladino N, Fainboim H, Theiler G, et al. Gender Susceptibility to Chronic Hepatitis C Virus Infection Associated with Interleukin 10 Promoter Polymorphism. J. Virol,2006,80:9144-9150.
[77]Thompson AJ, McHutchison JG. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). J Viral Hepat,2009,16:377-387.
[78]Qiu P, Sanfiorenzo V, Curry S, et al. Identification of HCV protease inhibitor resistance mutations by selection pressure-based method. Nucleic Acids Res,2009,37:e74.
[79]Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology,2009,50:1709-1718.
[80]Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology,2008,48: 1769-1778.
[81]Mogk A, Bukau B. Molecular chaperones:structure of a protein disaggregase. Cuur Biol,2004, 14(2):78-80.
[82]Van Eden W, Van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol,2005,5(4):318-320.
[83]Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell,2006, 125(3):443-451.
[84]Feige U, Polla BS. Hsp70-a muli-gene, multi-structure, multi-funcation family with potential clinical applications. Experientia,1994,50(6):979-986.
[85]Perez-Vargas, J., Romero, P., Lopez, S.& Arias, C.F. The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J. Virol,2006, 80:3322-3331.
[86]Dworniczak B, Mirault ME. Structure and expression of a human gene coding for a 71 kd heat shock'cognate'protein. Nucleic Acids Res,1987,15:5181-5197.
[87]Chromy LR, Pipas JM, Garcea RL. Chaperone-mediated in vitro assembly of Polyomavirus capsids. Proc Natl Acad Sci U S A,2003,100:10477-10482.
[88]Guerrero CA, Bouyssounade D, Zarate S,et al. Heat shock cognate protein 70 is involved in rotavirus cell entry. J. Virol,2002,76:4096-4102.
[89]Zarate S, Cuadras MA, Espinosa R, et al. Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5. J. Virol,2003,77:7254-7260.
[90]Ivanovic T, Agosto MA, Chandran K,et al. A role for molecular chaperone Hsc70 in reovirus outer capsid disassembly. J Biol Chem,2007,282:12210-12219.
[91]Jolanta B G, Mediyha S, Susanna C, et al. Activation of heat-shock response by an adenovirus is essential for virus replication. Nature,2000,407:207-211.
[92]Parent R, Qu X, Petit MA, et al. The heat shock cognate protein 70 is associated with hepatitis C virus particles and modulates virus infectivity. Hepatology,2009,49:1798-1809.
[93]Eddy EM. HSP70-2 heat-shock protein of mouse spermatogenic cells. J Exp Zool,1998,282: 261-271.
[94]Blight KJ, McKeating JA, Rice CM. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol,2002,76:13001-13014.
[95]Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med,2005,11:791-796.
[96]Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, et al. Complete replication of hepatitis C virus in cell culture. Science,2005,309:623-626.
[1]Gabuzda D H, Lawrence K, Langhoff E, et al. Role of vif in replication of human immunodeficiency virus type 1 in CD4-T lymphocytes[J]. J Virol,1992,66:6489-6495.
[2]Simon J H, Malim M H. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes[J]. J Virol,1996,70:5297-5305.
[3]Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein[J]. J Virol,1998,72:10251-10255.
[4]Simon J H M, Gaddis N C, Fouchier R A M, et al. Evidence for a newly discovered cellular anti-HIV-1 phenotype[J]. Nat Med,1998,4:1397-1400.
[5]Sheehy A M, Gaddis N C, Choi J D, et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein[J]. Nature,2002,418:646-650.
[6]Jarmuz A, Chester A, Bayliss J, et al. An anthropoid-specific locus of orphan C to U RNA editing enzymes on chromosome 22[J]. Genomics,2002,79:285-296.
[7]Cen S, Guo F, Niu M, et al. The interaction between HIV-1 Gag and APOBEC3G[J]. J Biol Chem, 2004,279:33177-33184.
[8]Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
[9]Yu Q, Ko"nig R, Pillai S, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome[J]. Nat Struct Mol Biol,2004,11:435-442.
[10]Mangeat B, Truelli P, Caron G, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts[J]. Nature,2003,424:99-103.
[11]Harris R S, Bishop K N, Sheehy A M, et al. DNA deamination mediates innate immunity to retroviral infection[J].Cell,2003,113:803-809.
[12]Zhang H, Yang B, Pomerantz R Z, et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA[J]. Nature,2003,424:94-98.
[13]Scha"fer A, Bogerd H P, Cullen B R. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor[J]. Virology,2004, 328:163-168.
[14]Burnett A, Spearman P. APOBEC3G multimers are recruited to the plasma membrane for packaging into human immunodeficiency virus type 1 virus-like particles in an RNA-dependent process requiring the NC basic linker[J]. J Virol,2007,81:5000-5013.
[15]Francisco N, Brooke B, Hui C, et al. Complementary function of the two catalytic domains of APOBEC3G.Virology,2005,333:374-386.
[16]Marin M, Rose K M, Kozak S L, et al. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation[J]. Nat Med,2003,9:1398-1403.
[17]Yu X, Yu Y, Liu B, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex[J]. Science,2003,302:1056-1060.
[18]Stopak K, de Noronha C, Yonemoto W, et al. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability[J]. Mol Cell,2003, 12:591-601.
[19]Sheehy A M, Gaddies N C, Malim M H. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif[J]. Nat Med,2003,9:1404-1407.
[20]Huthoff H, Malim M H. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and virion encapsidation. J Virol,2007, 81:3807-3815.
[21]Huthoff H, Malim MH. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and Virion encapsidation. J Virol,2007, 81(8):3807-3815.
[22]Cen S, Peng ZG, Li XY. Small molecular compounds inhibit HIV-1 replication through specifically stabilizing APOBEC3G. J Biol Chem,2010,285(22):16546-16552.
[23]Xiao Z, Ehrlich E, Luo K, et al. Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G. FASEB J,2007,21:217-222.
[24]Nathans R, Cao H, Sharova N, et al. Small-molecule inhibition of HIV-1 Vif. Nat Biotechnol, 2008,26:1187-1192.
[25]Ott DE. Cellular proteins detected in HIV-1. Rev. Med. Virol,2008,18:159-175.
1. Gabuzda D H, Lawrence K, Langhoff E, et al. Role of vif in replication of human immunodeficiency virus type 1 in CD4-T lymphocytes[J]. J Virol,1992,66:6489-6495.
2. Simon J H, Malim M H. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes[J]. J Virol,1996,70:5297-5305.
3. Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein[J]. J Virol,1998,72:10251-10255.
4. Simon J H M, Gaddis N C, Fouchier R A M, et al. Evidence for a newly discovered cellular anti-HIV-1 phenotype[J]. Nat Med,1998,4:1397-1400.
5. Sheehy A M, Gaddis N C, Choi J D, et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein[J]. Nature,2002,418:646-650.
6. Jarmuz A, Chester A, Bayliss J, et al. An anthropoid-specific locus of orphan C to U RNA editing enzymes on chromosome 22[J]. Genomics,2002,79:285-296.
7. Rogozin I B, Basu M K, Jordan I K, et al. APOBEC4, a new member of the AID/APOBEC family of polynucleotide(Deoxy) cytidine deaminases predicted by computational analysis[J]. Cell Cycle,2005,4:1281-1285.
8. Wedekind J E, Dance G S, Sowden M P, et al. Messenger RNA editing in mammals:new members of the APOBEC family seeking roles in the family business[J]. Trends Genet,2003, 19:207-216.
9. Liao W, Hong S H, Chan B H, et al. APOBEC-2, a cardiac-and skeletal musclespecific member of the cytidine deaminase supergene family[J]. Biochem Biophys Res Commun,1999, 260:398-404.
10. Yoshikawa K, Okazaki I M, Eto T, et al. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts[J]. Science,2002,296:2033-2036.
11. Cen S, Guo F, Niu M, et al. The interaction between HIV-1 Gag and APOBEC3G[J]. J Biol Chem,2004,279:33177-33184.
12. Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
13. Yu Q, Konig R, Pillai S, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome[J]. Nat Struct Mol Biol,2004,11:435-442.
14. Mangeat B, Truelli P, Caron G, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts[J]. Nature,2003,424:99-103.
15. Harris R S, Bishop K N, Sheehy A M, et al. DNA deamination mediates innate immunity to retroviral infection[J].Cell,2003,113:803-809.
16. Zhang H, Yang B, Pomerantz R Z, et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA[J]. Nature,2003,424:94-98.
17. Schrofelbauer B, Yu Q, Zeitlin S G, et al. Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases[J]. J Virol,2005, 79:10978-10987.
18. Scha"fer A, Bogerd H P, Cullen B R. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor[J]. Virology,2004, 328:163-168.
19. Burnett A, Spearman P. APOBEC3G multimers are recruited to the plasma membrane for packaging into human immunodeficiency virus type 1 virus-like particles in an RNA-dependent process requiring the NC basic linker[J]. J Virol,2007,81:5000-5013.
20. Huthoff H, Malim M H. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and virion encapsidation. J Virol,2007, 81:3807-3815.
21. Alce T M, Popik W. APOBEC3G is incorporated into virus-like particles by a direct interaction with HIV-1 Gag nucleocapsid protein[J]. J Biol Chem,2004,279:34083-34086.
22. Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
23. Zennou V, Perez-Caballero D, Go"ttlinger H, et al. APOBEC3G incorporation into human immunodeficiency virus type 1 particles[J].J Virol,2004,78:12058-12061.
24. Newman E N, Holmes R K, Craig H M, et al. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity[J]. Curr Biol,2005,15:166-170.
25. Guo F, Cen S, N Mei, et al. Inhibition of tRNA3Lys-Primed Reverse Transcription by Human APOBEC3G during Human Immunodeficiency Virus Type 1 Replication[J]. J Virol,2006, 80:11710-11722.
26. Luo Kun, Wang T, Liu B, et al. Cytidine deaminases APOBEC3G and APOBEC3F interact with HIV-1 integrase and inhibit proviral DNA formation[J]. J Virol,2007,81:7238-7248.
27. Stopak K, de Noronha C, Yonemoto W, et al. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability[J]. Mol Cell,2003, 12:591-601.
28. Sheehy A M, Gaddies N C, Malim M H. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif[J]. Nat Med,2003,9:1404-1407.
29. Marin M, Rose K M, Kozak S L, et al. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation[J]. Nat Med,2003,9:1398-1403.
30. Yu X, Yu Y, Liu B, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1
Vif-Cul5-SCF complex[J]. Science,2003,302:1056-1060.
31. Kao S, Khan M A, Miyaqi E, et al. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity[J]. J Virol,2003,77:11398-11407.
32. Kao S, Miyaqi E, Khan M A, et al. Production of infectious human immunodeficiency virus type 1 does not require depletion of APOBEC3G from virus-producing cells[J]. Retrovirology,2004, 1:27-39.
33. Mariani R, Chen D, Schrofelbauer B, et al. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif[J]. Cell,2003,114:21-31.
34. Bogerd H P, Doehle B P, Wiegand H L, et al. A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor[J]. Proc Natl Acad Sci U S A,2004,101:3770-3774.
35. Mangeat B, Turelli P, Liao S, et al. A single amino acid determinant governs the species-specific sensitivity of APOBEC3G to Vif action[J]. J Biol Chem,2004,279:14481-14483.
36. Xu H, Svarovskaia E S, Barr R, et al. A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion[J]. Proc Natl Acad Sci U S A,2004,101:5652-5657.
37. Palella F, Delaney K M, Moorman A C, et al. Declining morbidity and mortality among patients with advanced HIV infection[J]. HIV Outpatient Study Investigators, N Engl J Med,1998, 338:853-860.
38. Siliciano J D, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+T-cells[J]. Nat Med,2003,9:727-728.
39. Jin X, Brooks A, Chen H, et al. APOBEC3G/CEM15 (hA3G) mRNA levels associate inversely with human immunodeficiency virus viremia[J]. J Virol,2005,79:11513-11516.
40. Kieffer T L, Kwon P, Nettles R E, et al. G→A hypermutation in protease and reverse transcriptase regions of HIV-1 residing in resting CD4+ T-cells in vivo[J]. J Virol,2005, 79:1975-1980.
41. Rose K M, Marin M, Kozak S L, et al. Transcriptional regulation of APOBEC3G, acytidine deaminase that hypermutates human immunodeficiency virus[J]. J Biol Chem,2004, 279:41744-41749.
42. Peng G, Lei K J, Jin W, et al. Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti-HIV-1 activity[J]. J Exp Med,2006,203:41-46.
43. Harris RS, Liddament MT. Retroviral restriction by APOBEC proteins[J]. Nat Rev Immunol, 2004,4:868-877.
[2]Perz JF, Farrington LA, Pecoraro C, et al. Estimated global prevalence of hepatitis C virus infection.42nd Annual Meeting of the Infectious Diseases Society of America, Boston, MA, USA, Sept 30-Oct 3,2004.
[3]Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol,2006,45:529-538.
[4]Vaccine Research. Hepatitis C.
[5]Robertson B, Myers G, Howard C, et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses:proposals for standardization. International Committee on Virus Taxonomy. Arch Virol,1998,143:2493-2503.
[6]Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science,1989,244:359-362.
[7]Martell M, Esteban JI, Quer J, et al. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes:quasispecies nature of HCV genome distribution. J Virol,1992,66: 3225-3229.
[8]Pawloltsky JM. Hepatitis C virus population dynamics during infection. Curr. Top. Microbiol Immunol,2006,299:261-284.
[9]Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science,1998,282: 938-941.
[10]Levy S, Todd SC, Maecker HT. CD81 (TAPA-1):a molecule involved in signal transduction and cell adhesion in the immune system. Annu. Rev. Immunol,1998,16:89-109.
[11]Petracca R, Falugi F, Galli G, et al. Structure-function analysis of hepatitis C virus envelope-CD81 binding. J. Virol,2000,10:4824-4830.
[12]Scarselli E, Ansuini H, Cerino R, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J,2002,19:5017-5025.
[13]Rhainds D, Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. defining the rules for lipid traders. Int. J. Biochem. Cell Biol,2004,36:39-77.
[14]Yamada E, Montoya M, Schuettler CG, et al. Analysis of the binding of hepatitis C virus genotype la and 1b E2 glycoproteins to peripheral blood mononuclear cell subsets. J. Gen. Virol, 2005,86:2507-2512.
[15]Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science,1996,271:518-520.
[16]Gardner JP, Durso RJ, Arrigale RR, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc. Natl. Acad. Sci. U. S. A,2003,8:4498-4503.
[17]Lozach Y, Lortat-Jacob H, de Lacroix de Lavalette A, et al. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J. Biol. Chem,2003,22:20358-20366.
[18]Cormier EG, Durso RJ, Tsamis F, et al. L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc.Natl. Acad. Sci. U. S. A,2004,39:14067-14072.
[19]Evans MJ, Von Hahn T, Tscherne DM, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature,2007,446:801-805.
[20]Rijnbrand R, Bredenbeek P, Van der Straaten T, et al. Almost the entire 5'non-translated region of hepatitis C virus is required for cap-independent translation. FEBS Lett,1995,365:115-119.
[21]B.J. Yoo BJ, Spaete RR, Geballe AP, et al.5'end-dependent translation initiation of hepatitis C viral RNA and the presence of putative positive and negative translational control elements within the 5'untranslated region. Virology,1992,191:889-899.
[22]Hellen U, Pestova TV. Translation of hepatitis C virus RNA, J. Viral Hepatitis,1999,6:79-87.
[23]Lu HH, Wimmer E. Poliovirus chimeras replicating under the translational control of genetic elements of hepatitis C virus reveal unusual properties of the internal ribosomal entry site of hepatitis C virus, Proc. Natl. Acad. Sci. U. S. A,1996,93:1412-1417.
[24]Reynolds JE, Kaminski A, Kettinen HJ, et al. Unique features of internal initiation of hepatitis C virus RNA translation. EMBO J,1995,23:6010-6020.
[25]Walewski JL, Keller TR, Stump DD, et al. Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame. RNA,2001,7:710-721.
[26]Xu Z, Choi J, Yen TS, et al. Synthesis of a novel hepatitis C virus protein by ribosomal frameshift. EMBO J,2001,20:3840-3848.
[27]Varaklioti A, Vassilaki N, Georgopoulou U, et al. Alternate translation occurs within the core coding region of the hepatitis C viral genome. J. Biol. Chem,2002,277:17713-17721.
[28]Hussy P, Langen H, Mous J, et al. Hepatitis C virus core protein:carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase. Virology,1996,224:93-104.
[29]Weihofen A, Binns K, Lemberg MK, et al. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science,2002,296:2215-2218.
[30]Shi ST, Lee KJ, Aizaki H, et al. Hepatitis C virus RNA replication occurs on a detergent-resistant membrane that cofractionates with caveolin-2. J. Virol,2003,77:4160-4168.
[31]Pfeifer U, Thomssen R, Legler K, et al. Experimental non-A, non-B hepatitis:four types of cytoplasmic alteration in hepatocytes of infected chimpanzees. Virchows Arch., B Cell Pathol. Incl. Mol. Pathol,1980,33:233-243.
[32]Mottola G, Cardinali G, Ceccacci A, et al. Hepatitis C virus nonstructural proteins are localized in a modified endoplasmic reticulum of cells expressing viral subgenomic replicons. Virology,2002, 293:31-43.
[33]Watashi K, Ishii N, Hijikata M, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol. Cell,2005,19:111-122.
[34]Goh PY, Tan YJ, Lim SP, et al. Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. J. Virol, 2004,78:5288-5298.
[35]Hirano M, Kaneko S, Yamashita,HT. et al. Direct interaction between nucleolin and hepatitis C virus NS5B. J. Biol. Chem,2003,278:5109-5115.
[36]Kim S, Seol SK, Song OK, et al. An RNA-binding protein, hnRNP A1, and a scaffold protein, Septin 6, facilitate hepatitis C virus replication, J. Virol,2007,81:3852-3865.
[37]Ali N, Siddiqui A. Interaction of polypyrimidine tract-binding protein with the 5'noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation. J. Virol,1995,69:6367-6375.
[38]Ito T, Lai MM. Determination of the secondary structure of and cellular protein binding to the 3'-untranslated region of the hepatitis C virus RNA genome. J. Virol,1997,71:8698-8706.
[39]Kaito M, Wastanabe S, Tsukiyama-Kohara K, et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J. Gen. Virol,1994,75:1755-1760.
[40]Shimizu YK, Feinstone SM, Kohara M, et al. Hepatitis C virus:detection of intracellular virus particles by electron microscopy. Hepatology,1996,23:205-209.
[41]Serafino A, Valli MB, Andreola F, et al. Suggested role of the Golgi apparatus and endoplasmic reticulum for crucial sites of hepatitis C virus replication in human lymphoblastoid cells infected in vitro. J. Med. Virol,2003,70:31-41.
[42]Sato K, Okamoto H, Aihara S, et al. Demonstration of sugar moiety on the surface of hepatitis C virions recovered from the circulation of infected humans. Virology,1993,196:354-357.
[43]Simmonds P. Viral heterogeneity of the hepatitis C virus. Journal of Hepatology,1999,31:54-60.
[44]Houghton M. Hepatitis C viruses. In:Fields BN, Knipe DM, Howley PM, eds. Fields Virology, 3rd ed. Philadelphia, Lippincott-Raven,1996:1035-1058.
[45]Mondelli MU, Silini E. Clinical significance of hepatitis C virus genotypes. Journal of Hepatology,1999,31:65-70.
[46]US Department of Health and Human Services.Centers for Disease Control and Prevention. Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease. Morbidity and Mortality Weekly Report,1998,47.
[47]World Health Organization. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in Collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. Journal of Viral Hepatology,1999,6:35-47.
[48]National Institutes of Health. Consensus Development Conference Statement:Management of Hepatitis C:2002, June 10-12.2002,
[50]Davis GL, Balart LA., Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon a. A multicenter randomized, controlled trial. Hepatitis. Interventional.Therapy. Group. N. Engl. J. Med,1989,321:1501-1506.
[51]McHutchison JG, Stuart C, Schiff ER, et al. Interferon a-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N. Engl. J. Med,1998,339:1485-1492.
[52]Zeuzem, S. Feinman SV, Rasenack J,. et al. Peginterferon α-2a in patients with chronic hepatitis C. N. Engl. J. Med,2000,343:1666-1672.
[53]Zic, I. Peginterferon a/ribavirin combination therapy for the treatment of hepatitis C infection. Gastroenterol. Nurs,2005,28:317-328.
[54]Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon a-2b to interferon a-2b as initial treatment for chronic hepatitis C. Hepatology 34, 395-403(2001).
[55]Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon a-2b plus ribavirin compared with interferon a-2b plus ribavirin for initial treatment of chronic hepatitis C:a randomised trial. Lancet, 2001,358:958-965.
[56]Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon a-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med.347,975-982 (2002).
[57]Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C:efficacy, side effects, and complications. Gut,2006,55:1350-1359.
[58]Balan V, Nelson DR, Sulkowski MS, et al. A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-a fusion protein in chronic hepatitis C patients who have failed previous interferon-α-based therapy. Antivir. Ther,2006,11:35-45.
[59]Zeuzem S, Yoshida EM, Benhamou Y, et al. Sustained virologic response rates with albinterferon α-2b plus ribavirin treatment in IFN-naive, chronic hepatitis C genotype I patients. Hepatology,2007, 46(Suppl.1),317A.
[60]Robert GG. Treating HCV with ribavirin analogues and ribavirin-like molecules. Journal of Antimicrobial Chemotherapy,2006,57:8-13.
[61]Benhamou Y, Pockros P, Rodrieuez TM, et al. The safety and efficacy of viramidine(?) plus pegylated interferon α-2b versus ribavirin plus pegylated interferon α-2b in therapynaive patients infected with HCV:Phase 3 results. J. Hepatol,2006,44 (Suppl.2), S273.
[62]Marcellin P, Lurie Y, Rodrigues TM, et al. The safety and efficacy of taribavirin plus pegylated interferon α-2a versus ribavirin plus pegylated interferon α-2a in therapy-naive patients infected with HCV:Phase 3 results. J. Hepatol,2007,46 (Suppl.1), S7.
[63]Paulsen RB, Seth PP, Swayze EE, et al. Inhibitor-induced structural change in the HCV IRES domain Ⅱa RNA. Proc Natl Acad Sci U S A,2010,107:7263-7268.
[64]Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature,2003,426:186-189.
[65 Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol,2009,6:403-411.
[66]Mederacke I, Wedemeyer H, Manns MP. Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. Curr Opin Investig Drugs,2009,10:181-189.
[67]Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med,2009,360:1839-1850.
[68]McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med,2009,360:1827-1838.
[69]Olsen DB, Carroll SS, Handt L, et al. HCV antiviral activity and resistance analysis in chronically infected chimpanzees treated with NS3/4A protease and NS5B polymerase inhibitors. J. Hepatol,2007,46 (Suppl.1), S298.
[70]Roberts S, Cooksley G, Shaw D, et al. Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV patients. J. Hepatol, 2006,44 (Suppl.2), S269.
[71]Afdhal N, Brien CO, Godofsky E, et al. Valopicitabine (NM283), alone or with peg-interferon, compared to peg-interferon/ribavirin (pegIFN/RBV) retreatment in hepatitis C patients with prior non-response to pegIFN/RBV:week 24 results. J. Hepatol.44 (Suppl.2), S19(2006).
[72]Dieterich D, Lawitz E, Nguyen T, et al. Early clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection:first results from a Phase Ⅱb trial. J. Hepatol,2006,44 (Suppl.2), S271.
[73]Kandil S, Biondaro S, Vlachakis D, et al. Discovery of a novel HCV helicase inhibitor by a de novo drug design approach. Bioorg Med Chem Lett,2009,19::2935-2937.
[74]Luscombe CA, Huang ZH, Murray MG, et al. A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-a-2b and nucleoside analogues. Antiviral Research,2010,86:144-153.
[75]McHutchison JG, Bartenschlager R, Patel K, et al. The face of future hepatitis C antiviral drug development:recent biological and virologic advances and their translation to drug development and clinical practice. J. Hepatol,2006,44:411-421.
[76]Paladino N, Fainboim H, Theiler G, et al. Gender Susceptibility to Chronic Hepatitis C Virus Infection Associated with Interleukin 10 Promoter Polymorphism. J. Virol,2006,80:9144-9150.
[77]Thompson AJ, McHutchison JG. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). J Viral Hepat,2009,16:377-387.
[78]Qiu P, Sanfiorenzo V, Curry S, et al. Identification of HCV protease inhibitor resistance mutations by selection pressure-based method. Nucleic Acids Res,2009,37:e74.
[79]Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology,2009,50:1709-1718.
[80]Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology,2008,48: 1769-1778.
[81]Mogk A, Bukau B. Molecular chaperones:structure of a protein disaggregase. Cuur Biol,2004, 14(2):78-80.
[82]Van Eden W, Van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol,2005,5(4):318-320.
[83]Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell,2006, 125(3):443-451.
[84]Feige U, Polla BS. Hsp70-a muli-gene, multi-structure, multi-funcation family with potential clinical applications. Experientia,1994,50(6):979-986.
[85]Perez-Vargas, J., Romero, P., Lopez, S.& Arias, C.F. The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J. Virol,2006, 80:3322-3331.
[86]Dworniczak B, Mirault ME. Structure and expression of a human gene coding for a 71 kd heat shock'cognate'protein. Nucleic Acids Res,1987,15:5181-5197.
[87]Chromy LR, Pipas JM, Garcea RL. Chaperone-mediated in vitro assembly of Polyomavirus capsids. Proc Natl Acad Sci U S A,2003,100:10477-10482.
[88]Guerrero CA, Bouyssounade D, Zarate S,et al. Heat shock cognate protein 70 is involved in rotavirus cell entry. J. Virol,2002,76:4096-4102.
[89]Zarate S, Cuadras MA, Espinosa R, et al. Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5. J. Virol,2003,77:7254-7260.
[90]Ivanovic T, Agosto MA, Chandran K,et al. A role for molecular chaperone Hsc70 in reovirus outer capsid disassembly. J Biol Chem,2007,282:12210-12219.
[91]Jolanta B G, Mediyha S, Susanna C, et al. Activation of heat-shock response by an adenovirus is essential for virus replication. Nature,2000,407:207-211.
[92]Parent R, Qu X, Petit MA, et al. The heat shock cognate protein 70 is associated with hepatitis C virus particles and modulates virus infectivity. Hepatology,2009,49:1798-1809.
[93]Eddy EM. HSP70-2 heat-shock protein of mouse spermatogenic cells. J Exp Zool,1998,282: 261-271.
[94]Blight KJ, McKeating JA, Rice CM. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol,2002,76:13001-13014.
[95]Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med,2005,11:791-796.
[96]Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, et al. Complete replication of hepatitis C virus in cell culture. Science,2005,309:623-626.
[1]Gabuzda D H, Lawrence K, Langhoff E, et al. Role of vif in replication of human immunodeficiency virus type 1 in CD4-T lymphocytes[J]. J Virol,1992,66:6489-6495.
[2]Simon J H, Malim M H. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes[J]. J Virol,1996,70:5297-5305.
[3]Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein[J]. J Virol,1998,72:10251-10255.
[4]Simon J H M, Gaddis N C, Fouchier R A M, et al. Evidence for a newly discovered cellular anti-HIV-1 phenotype[J]. Nat Med,1998,4:1397-1400.
[5]Sheehy A M, Gaddis N C, Choi J D, et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein[J]. Nature,2002,418:646-650.
[6]Jarmuz A, Chester A, Bayliss J, et al. An anthropoid-specific locus of orphan C to U RNA editing enzymes on chromosome 22[J]. Genomics,2002,79:285-296.
[7]Cen S, Guo F, Niu M, et al. The interaction between HIV-1 Gag and APOBEC3G[J]. J Biol Chem, 2004,279:33177-33184.
[8]Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
[9]Yu Q, Ko"nig R, Pillai S, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome[J]. Nat Struct Mol Biol,2004,11:435-442.
[10]Mangeat B, Truelli P, Caron G, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts[J]. Nature,2003,424:99-103.
[11]Harris R S, Bishop K N, Sheehy A M, et al. DNA deamination mediates innate immunity to retroviral infection[J].Cell,2003,113:803-809.
[12]Zhang H, Yang B, Pomerantz R Z, et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA[J]. Nature,2003,424:94-98.
[13]Scha"fer A, Bogerd H P, Cullen B R. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor[J]. Virology,2004, 328:163-168.
[14]Burnett A, Spearman P. APOBEC3G multimers are recruited to the plasma membrane for packaging into human immunodeficiency virus type 1 virus-like particles in an RNA-dependent process requiring the NC basic linker[J]. J Virol,2007,81:5000-5013.
[15]Francisco N, Brooke B, Hui C, et al. Complementary function of the two catalytic domains of APOBEC3G.Virology,2005,333:374-386.
[16]Marin M, Rose K M, Kozak S L, et al. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation[J]. Nat Med,2003,9:1398-1403.
[17]Yu X, Yu Y, Liu B, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex[J]. Science,2003,302:1056-1060.
[18]Stopak K, de Noronha C, Yonemoto W, et al. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability[J]. Mol Cell,2003, 12:591-601.
[19]Sheehy A M, Gaddies N C, Malim M H. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif[J]. Nat Med,2003,9:1404-1407.
[20]Huthoff H, Malim M H. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and virion encapsidation. J Virol,2007, 81:3807-3815.
[21]Huthoff H, Malim MH. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and Virion encapsidation. J Virol,2007, 81(8):3807-3815.
[22]Cen S, Peng ZG, Li XY. Small molecular compounds inhibit HIV-1 replication through specifically stabilizing APOBEC3G. J Biol Chem,2010,285(22):16546-16552.
[23]Xiao Z, Ehrlich E, Luo K, et al. Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G. FASEB J,2007,21:217-222.
[24]Nathans R, Cao H, Sharova N, et al. Small-molecule inhibition of HIV-1 Vif. Nat Biotechnol, 2008,26:1187-1192.
[25]Ott DE. Cellular proteins detected in HIV-1. Rev. Med. Virol,2008,18:159-175.
1. Gabuzda D H, Lawrence K, Langhoff E, et al. Role of vif in replication of human immunodeficiency virus type 1 in CD4-T lymphocytes[J]. J Virol,1992,66:6489-6495.
2. Simon J H, Malim M H. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes[J]. J Virol,1996,70:5297-5305.
3. Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein[J]. J Virol,1998,72:10251-10255.
4. Simon J H M, Gaddis N C, Fouchier R A M, et al. Evidence for a newly discovered cellular anti-HIV-1 phenotype[J]. Nat Med,1998,4:1397-1400.
5. Sheehy A M, Gaddis N C, Choi J D, et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein[J]. Nature,2002,418:646-650.
6. Jarmuz A, Chester A, Bayliss J, et al. An anthropoid-specific locus of orphan C to U RNA editing enzymes on chromosome 22[J]. Genomics,2002,79:285-296.
7. Rogozin I B, Basu M K, Jordan I K, et al. APOBEC4, a new member of the AID/APOBEC family of polynucleotide(Deoxy) cytidine deaminases predicted by computational analysis[J]. Cell Cycle,2005,4:1281-1285.
8. Wedekind J E, Dance G S, Sowden M P, et al. Messenger RNA editing in mammals:new members of the APOBEC family seeking roles in the family business[J]. Trends Genet,2003, 19:207-216.
9. Liao W, Hong S H, Chan B H, et al. APOBEC-2, a cardiac-and skeletal musclespecific member of the cytidine deaminase supergene family[J]. Biochem Biophys Res Commun,1999, 260:398-404.
10. Yoshikawa K, Okazaki I M, Eto T, et al. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts[J]. Science,2002,296:2033-2036.
11. Cen S, Guo F, Niu M, et al. The interaction between HIV-1 Gag and APOBEC3G[J]. J Biol Chem,2004,279:33177-33184.
12. Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
13. Yu Q, Konig R, Pillai S, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome[J]. Nat Struct Mol Biol,2004,11:435-442.
14. Mangeat B, Truelli P, Caron G, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts[J]. Nature,2003,424:99-103.
15. Harris R S, Bishop K N, Sheehy A M, et al. DNA deamination mediates innate immunity to retroviral infection[J].Cell,2003,113:803-809.
16. Zhang H, Yang B, Pomerantz R Z, et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA[J]. Nature,2003,424:94-98.
17. Schrofelbauer B, Yu Q, Zeitlin S G, et al. Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases[J]. J Virol,2005, 79:10978-10987.
18. Scha"fer A, Bogerd H P, Cullen B R. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor[J]. Virology,2004, 328:163-168.
19. Burnett A, Spearman P. APOBEC3G multimers are recruited to the plasma membrane for packaging into human immunodeficiency virus type 1 virus-like particles in an RNA-dependent process requiring the NC basic linker[J]. J Virol,2007,81:5000-5013.
20. Huthoff H, Malim M H. Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and virion encapsidation. J Virol,2007, 81:3807-3815.
21. Alce T M, Popik W. APOBEC3G is incorporated into virus-like particles by a direct interaction with HIV-1 Gag nucleocapsid protein[J]. J Biol Chem,2004,279:34083-34086.
22. Svarovskaia E S, Xu H, Mbisa J L, et al. Human apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs[J]. J Biol Chem,2004,279:35822-35828.
23. Zennou V, Perez-Caballero D, Go"ttlinger H, et al. APOBEC3G incorporation into human immunodeficiency virus type 1 particles[J].J Virol,2004,78:12058-12061.
24. Newman E N, Holmes R K, Craig H M, et al. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity[J]. Curr Biol,2005,15:166-170.
25. Guo F, Cen S, N Mei, et al. Inhibition of tRNA3Lys-Primed Reverse Transcription by Human APOBEC3G during Human Immunodeficiency Virus Type 1 Replication[J]. J Virol,2006, 80:11710-11722.
26. Luo Kun, Wang T, Liu B, et al. Cytidine deaminases APOBEC3G and APOBEC3F interact with HIV-1 integrase and inhibit proviral DNA formation[J]. J Virol,2007,81:7238-7248.
27. Stopak K, de Noronha C, Yonemoto W, et al. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability[J]. Mol Cell,2003, 12:591-601.
28. Sheehy A M, Gaddies N C, Malim M H. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif[J]. Nat Med,2003,9:1404-1407.
29. Marin M, Rose K M, Kozak S L, et al. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation[J]. Nat Med,2003,9:1398-1403.
30. Yu X, Yu Y, Liu B, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1
Vif-Cul5-SCF complex[J]. Science,2003,302:1056-1060.
31. Kao S, Khan M A, Miyaqi E, et al. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity[J]. J Virol,2003,77:11398-11407.
32. Kao S, Miyaqi E, Khan M A, et al. Production of infectious human immunodeficiency virus type 1 does not require depletion of APOBEC3G from virus-producing cells[J]. Retrovirology,2004, 1:27-39.
33. Mariani R, Chen D, Schrofelbauer B, et al. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif[J]. Cell,2003,114:21-31.
34. Bogerd H P, Doehle B P, Wiegand H L, et al. A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor[J]. Proc Natl Acad Sci U S A,2004,101:3770-3774.
35. Mangeat B, Turelli P, Liao S, et al. A single amino acid determinant governs the species-specific sensitivity of APOBEC3G to Vif action[J]. J Biol Chem,2004,279:14481-14483.
36. Xu H, Svarovskaia E S, Barr R, et al. A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion[J]. Proc Natl Acad Sci U S A,2004,101:5652-5657.
37. Palella F, Delaney K M, Moorman A C, et al. Declining morbidity and mortality among patients with advanced HIV infection[J]. HIV Outpatient Study Investigators, N Engl J Med,1998, 338:853-860.
38. Siliciano J D, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+T-cells[J]. Nat Med,2003,9:727-728.
39. Jin X, Brooks A, Chen H, et al. APOBEC3G/CEM15 (hA3G) mRNA levels associate inversely with human immunodeficiency virus viremia[J]. J Virol,2005,79:11513-11516.
40. Kieffer T L, Kwon P, Nettles R E, et al. G→A hypermutation in protease and reverse transcriptase regions of HIV-1 residing in resting CD4+ T-cells in vivo[J]. J Virol,2005, 79:1975-1980.
41. Rose K M, Marin M, Kozak S L, et al. Transcriptional regulation of APOBEC3G, acytidine deaminase that hypermutates human immunodeficiency virus[J]. J Biol Chem,2004, 279:41744-41749.
42. Peng G, Lei K J, Jin W, et al. Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti-HIV-1 activity[J]. J Exp Med,2006,203:41-46.
43. Harris RS, Liddament MT. Retroviral restriction by APOBEC proteins[J]. Nat Rev Immunol, 2004,4:868-877.