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

目前针对丙型肝炎病毒的实验性疗法包括利巴韦林 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不是 知道的 在项目I中描述的发现，HCV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。 该项目将利用丰富的 南加州大学医疗设施的临床资源，以检查四个 患者组：（1）HCV感染和血清升高的患者 转氨酶（ALT）水平;（2）利巴韦林治疗患者;（3） 用α-干扰素治疗的患者;（4）合并感染HIV的患者 和HCV。来自这些患者的肝活检标本将 检测各种TNFR的表达，包括TNFR I，TNFR II， 抗病毒蛋白-β受体和Fas、CD 30及各种HCV病毒抗原。 还将检查其淋巴细胞亚群。 血清 将检查这些患者的HCV基因型和RNA水平， 可能存在可溶性CD 30和TNFR。 这些免疫 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。 本研究与项目I密切相关，并提供临床 确认项目I中拟定的体外研究。 这些 这些研究可能构成下一代的概念基础， 丙型肝炎病毒的治疗，这是一个主要的目标， 丙型肝炎合作研究中心。 而且 PI的经验。这一项目将使密切合作 与其他潜在的丙型肝炎研究中心在该国。

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.