De Francesco R, Neddermann P, Tomei L, Steinkühler C, Gallinari P, Folgori A
Istituto di Ricerche di Biologia Molecolare, Rome, Italy.
Semin Liver Dis. 2000;20(1):69-83. doi: 10.1055/s-2000-9504.
Infection with the hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. The viral genome, a positive-sense, single-stranded, 9.6-kb long RNA molecule, is translated into a single polyprotein of about 3,000 amino acids. The viral polyprotein is proteoytically processed to yield all the mature viral gene products. The genomic order of HCV has been determined to be C-->E1-->E2-->p7-->NS2-->NS3-->NS4A-->NS4B-->NS5A++ +-->NS5B. C, E1, and E2 are the virion structural proteins. Whereas the function of p7 is currently unknown, NS2 to NS5B are thought to be the nonstructural proteins. Generation of the mature nonstructural proteins relies on the activity of viral proteinases. Cleavage at the NS2-NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining downstream cleavages are effected by a serine proteinase contained also within the N-terminal region of NS3. NS3, in addition, contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that acts as a cofactor of the proteinase. Although no function has yet been attributed to NS4B, NS5A has been recently suggested to be involved in mediating the resistance of the HCV to the action of interferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase. This article reviews the current understanding of the structure and the function of the various HCV nonstructural proteins with particular emphasis on their potential as targets for the development of novel antiviral agents and vaccines.
丙型肝炎病毒（HCV）感染是全球范围内非甲非乙型肝炎的主要病因。病毒基因组是一种正义单链、9.6 kb长的RNA分子，被翻译成一个约3000个氨基酸的单一多聚蛋白。病毒多聚蛋白经蛋白酶加工后产生所有成熟的病毒基因产物。HCV的基因组顺序已确定为C→E1→E2→p7→NS2→NS3→NS4A→NS4B→NS5A++ +→NS5B。C、E1和E2是病毒粒子的结构蛋白。虽然p7的功能目前尚不清楚，但NS2至NS5B被认为是非结构蛋白。成熟非结构蛋白的产生依赖于病毒蛋白酶的活性。NS2-NS3连接处的切割由NS2和NS3 N端编码的金属依赖性自催化蛋白酶完成。其余下游切割由NS3 N端区域内的丝氨酸蛋白酶完成。此外，NS3在其C端含有一个RNA解旋酶结构域。NS3与NS4A形成异源二聚体复合物。后者是一种膜蛋白，作为蛋白酶的辅因子。虽然尚未确定NS4B的功能，但最近有人提出NS5A参与介导HCV对干扰素作用的抗性。最后，NS5B蛋白已被证明是病毒RNA依赖性RNA聚合酶。本文综述了目前对各种HCV非结构蛋白结构和功能的理解，特别强调了它们作为新型抗病毒药物和疫苗开发靶点的潜力。
