IMMUNE CONTROL OF EQUINE INFECTIOUS ANEMIA LENTIVIRUS

拟议研究的总体目标是描述免疫 可以控制慢病毒感染的机制。 慢病毒系统 研究的对象是马的EIAV病毒血症， 发热、贫血、血小板减少和肝脏淋巴细胞病变 和其他器官。 大多数马终止初始病毒血症和复发 最终成为无症状的携带者，病毒水平非常低。 表明淋巴细胞反应控制EIAV的数据包括观察 患有遗传性严重联合免疫缺陷的马驹 不能控制EIAV感染后的初始病毒血症， 正常马驹，和EIAV携带者的皮质类固醇治疗诱导 病毒血症和疾病。 将通过试验剖析EIAV的免疫控制 假设CD 8+细胞毒性T淋巴细胞（CTL）控制EIAV， 感染马的疾病 即使有效的疫苗可能 诱导几种重要的保护性免疫功能， 目前的知识是了解慢病毒在体内的作用， 特异性MHC限制性CD 8 + CTL控制感染。 我们 对Env和Gag/PR蛋白的MHC限制性CD 8 + CTL的证明 来自EIAV感染的马的未刺激的PBMC中的表位提供了 有机会获得关于其在控制 慢病毒感染 这些数据可能适用于其他慢病毒 包括HIV-1，其中对CTL的体内作用的剖析更多 难 使用来自EIAV感染马的CD 8 + CTL将促进 病毒感染过程中识别的免疫显性表位的鉴定 用于诱导所需CTL的对照。 最后，关于 CD 8 + CTL的体内作用可以通过挑战 用同源和异源EIAV免疫这些马， 确定CD 8 + T淋巴细胞耗竭是否会阻止 感染马的初始病毒血症。

The overall goal of the proposed research is to delineate immune mechanisms that can control lentiviral infections. The lentiviral system to be studied is EIAV in horses which has episodes of viremia resulting in fever, anemia, thrombocytopenia and lymphocytic lesions in the liver and other organs. Most horses terminate initial viremia and recurrences to eventually become asymptomatic carriers with very low levels of virus. Data indicating lymphocyte responses control EIAV include the observation that foals with genetically based severe combined immunodeficiency can not control the initial viremia following EIAV infection, in contrast to normal foals, and corticosteroid treatment of EIAV in carriers induces viremia and disease. Immune control of EIAV will be dissected by testing the assumption that CD8+ cytotoxic T lymphocytes (CTL) control EIAV and disease in infected horses. Even though effective vaccines will likely induce several important protective immune functions, a major gap in current knowledge is understanding the in vivo role of lentiviral- specific MHC-restricted CD8+ CTL in controlling infections. Our demonstration of MHC-restricted CD8+ CTL to Env and Gag/PR protein epitopes in unstimulated PBMC from EIAV infected horses provides an opportunity to obtain definitive information on their role in controlling this lentiviral infection. Such data may apply to other lentiviruses including HIV-1 where dissection of the in vivo role of CTL is more difficult. Use of CD8+ CTL from EIAV infected horses will facilitate identification of the immunodominant epitopes recognized during virus control for use in inducing the desired CTL. Finally, questions about the in vivo role of CD8+ CTL can be further evaluated by challenging these immunized horses with homologous and heterologous EIAV, and by determining if CD8+ T lymphocyte depletion will prevent termination of initial viremia in infected horses.