ADOPTIVE TRANSFER OF CD8+ CTLS TO CONTROL EIAV

研究建议：本研究的长期目标是确定 CTL在控制EIAV中的作用，EIAV是一种引起马的慢病毒 以反复发作的病毒血症为特征的持续性感染 并发发烧、血小板减少和贫血。感染EIAV的马匹 最终控制病毒血症和相关的临床疾病，并保持 终身隐形携带者。使用受严重感染的小马驹工作 联合免疫缺陷(SCID)已表明淋巴细胞反应是 用来终止急性感染后的病毒血症。此外, 持续的免疫控制机制可能是导致 保持看不见的载体状态，如复发所证明的 免疫抑制后的临床疾病。事实上，EIAV- 检测到特定的CD8+CTL同时终止 急性感染后的初始病毒血症，在出现 中和抗体，提示CTL参与了对霍乱的控制 病毒血症。此外，隐性携带者PBMC中存在EIAV特异性CTLm。 这项拟议的研究将检验EIAV特异性CD8+ CTL可预防或减少EIAV攻击后的病毒血症。在 来自PBMC的特异性AIMS、Env和GAG/PR特异性CD8+CTL 将使用逆转录病毒来选择、刺激和扩大携带者 载体转导的自体马肾刺激细胞 过继转移到ELA-A相合的SCID马驹。然后这些小马驹就会 感染EIAV并测定其保护效果。如果小马驹 是受保护的，CD8+CTL特异性的保护作用 保守的Gag蛋白p15、p26a和p26b将被评估。结果是 这项研究的成果将有助于深入了解免疫机制。 控制其他慢病毒感染，包括艾滋病毒-1。

Research Proposal: The long-term goal of this research is to define the role of CTLs in the control of EIAV, a lentivirus of horses which cause a persistent infection characterized by recurrent episodes of viremia with concurrent fever, thrombocytopenia, and anemia. Horses infected with EIAV eventually control the viremia and associated clinical disease, and remain lifelong inapparent carriers. Work using foals affected with severe combined immunodeficiency (SCID) has shown that lymphocyte responses are required to terminate the viremia following acute infection. In addition, continued immunologic control mechanisms are likely responsible for maintenance of the inapparent carrier state, as evidenced by recrudescence of clinical disease following immunosuppression. The fact that EIAV- specific CD8+ CTLs are detected con-incident with the termination of the initial viremia following acute infection, prior to the appearance of neutralizing antibody, suggests that CTLs are involved in control of viremia. In addition, inapparent carriers have EIAV-specific CTLm in PBMC. The proposed research will test the hypothesis that EIAV-specific CD8+ CTLs will prevent or reduce viremia following EIAV challenge. In the specific aims, Env and Gag/Pr-specific CD8+ CTLs from PBMC from inapparent carriers will be selected, stimulated and expanded using retroviral vector-transduced autologous equine kidney stimulator cells, and adoptively transferred to ELA-A matched SCID foals. These foals will then be infected with EIAV and the protective effects determined. If the foals are protected, the protective effects of CD8+ CTLs specific for the conserved Gag proteins p15, p26a, and p26b will be evaluated. The results of this research should provide insight into the mechanisms of immune control of other lentiviral infections, including HIV-1.