HEPATITIS C VIRUS MECHANISMS OF LIVER INJURY--EFFECTS OF THERAPY IN HUMANS

目前治疗丙型肝炎病毒的实验疗法包括利巴韦林 和α-干扰素；然而，对这些疗法的反应是 变量。决定治疗效果的因素并不是 为人所知。项目I中描述的发现丙型肝炎病毒核心蛋白 与肿瘤坏死因子受体(TNFR)家族成员相互作用 为确定这些药物的疗效提供了潜在的基础。 不同患者的治疗方法。该项目将利用丰富的 南加州大学医疗机构提供的临床资源可用于检查四个 患者组：(1)丙型肝炎病毒感染和血清升高患者 丙氨酸氨基转移酶(ALT)；(2)利巴韦林治疗；(3) 接受α-干扰素治疗的患者；(4)合并感染艾滋病毒的患者 和丙型肝炎病毒。从这些患者身上提取的肝活检样本将被 检测各种TNFR的表达，包括TNFR I，TNFR II， 淋巴毒素-β受体与Fas、CD30及各种丙型肝炎病毒抗原。 他们还将接受淋巴细胞亚群的检查。血清 将对这些患者进行丙型肝炎病毒基因型和RNA水平的检查，以及 可能存在可溶性CD30和TNFR。这些免疫学 参数将与患者的临床状态相关， 包括ALT水平、对干扰素或利巴韦林治疗的反应性。 这项研究与项目I密切相关，并提供了临床 确认项目I中提议的体外研究。这些 研究可能形成下一代 治疗丙型肝炎病毒，这是世界银行的主要目标之一 拟建丙型肝炎合作研究中心。此外， 这个项目的私家侦探的经验将使密切合作成为可能 与该国其他潜在的丙型肝炎研究中心合作。

Current experimental therapies for hepatitis C virus includes ribavirin and alpha-interferon; however, the responses to these therapies are variable. The factors determining the efficacy of the therapies are not known. The finding described in Project I that the HCV core protein interacts with members of tumor necrosis factor receptor (TNFR) family provides a potential basis for determining the efficacy of these therapies in different patients. This project will utilize abundant clinical resources available at USC medical facilities to examine four groups of patients: (1) patients with HCV infection and elevated serum aminotransferase (ALT) level; (2) patients treated with ribavirin; (3) patients treated with alpha-interferon; (4) patients coinfected with HIV and HCV. Liver biopsy specimens derived from these patients will be examined for the expression of various TNFRs, including TNFR I, TNFR II, lymphotoxin-beta receptor and Fas, CD30 and various HCV viral antigens. They will also be examined with respect to the lymphocyte subsets. Sera from these patients will be examined for HCV genotype and RNA level, and the possible presence of soluble CD30 and TNFR. These immunological parameters will be correlated with the patients' clinical status, including ALT level, responsiveness to interferon or ribavirin therapy. This study is linked closely with Project I, and provides clinical confirmation for the in vitro studies proposed in Project I. These studies may form the conceptual basis for the next generation of therapies for hepatitis C virus, which is one of the major goals of the proposed Hepatitis C Cooperative Research Centers. Furthermore, the experience of the P.I. for this project will enable close cooperation with other potential Hepatitis C Research Centers in the country.