HCV Nonstructural Proteins and Host Protein Secretion

丙型肝炎病毒（HCV）是世界范围内肝癌的主要原因之一。由于缺乏方便的动物模型或可靠的组织培养系统来繁殖病毒，对HCV复制的研究受到阻碍。研究者们一直关注HCV基因的表达以进行功能和结构研究。迄今为止，大多数HCV非结构蛋白都定位于内质网（ER）。因此，推测HCV NS 4 A/B前体蛋白的表达导致ER样区室的肿胀并抑制ER和高尔基体之间的蛋白运输。因此，很可能HCV/NS 4A/B o=前体蛋白抑制细胞分泌途径并修饰细胞内区室以形成病毒RNA复制复合物。在这个提议中，肿胀的细胞内室的性质和它们与HCV NS 4A/B前体蛋白的关系将被研究。还将检查其他HCV非结构蛋白（NS 2/3/4A、NS 4 B/5A、NS 4 B/5A、NS 4A和NS 5 B）抑制蛋白运输的能力。使用MHC I类分子，将测试HCV蛋白的这种抑制的特异性。将对BVDV同源蛋白进行类似研究，BVDV是一种可方便安全地在组织培养物中生长的黄病毒。从这些研究中获得的信息将有助于选择抑制剂或发病机制。

Hepatitis C virus (HCV) is one of the leading causes of liver cancer worldwide. Studies on HCV replication have been hampered by the lack of a convenient animal model or a reliable tissue culture system to propagate the virus. Investigators have focused on expression of HCV genes for functional and structural studies Most of the HCV non- structural proteins examined so far have been localized to the endoplasmic reticulum (ER). It is assumed therefore that expression of HCV NS4A/B precursor proteins results in the swelling of ER-like compartments and inhibits protein traffic between ER and Golgi apparatus. Thus, it is likely that HCV/NS4A/B o=precursor proteins inhibit cellular secretory pathway and modify intracellular compartments to form viral RNA replication complexes. In this proposal, the nature of the swollen intracellular compartments and their relationship to the HCV NS4A/B precursor proteins will be investigated. The ability of other HCV non-structural proteins (NS2/3/4A, NS4B/5A, NS4B/5A, NS4A and NS5B) to inhibit protein traffic will also be examined. Using MHC class I molecules, the specificity of this inhibition by HCV proteins will be tested. Similar studies will be done with homologous proteins of BVDV, a flavivirus that can be conveniently and safely be grown in tissue culture. Information gained from these studies will be useful in the selection of inhibitors or pathogenesis.