IMMUNE CONTROL OF CAE LENTIVIRUS

这项提议验证了聚焦细胞介导免疫的假设， 对纯化慢病毒表面（SU）免疫的反应 糖蛋白将控制病毒复制和疾病， 用同源和异源病毒攻击感染。研究 计划是关注抗原特异性辅助性T细胞（Th）1淋巴细胞反应 通过增强γ干扰素（IFN γ）在体内的产生， 免疫时间。一种痘苗病毒载体和质粒DNA表达 将评价IFN γ cDNA以增强体内IFN γ产生。 该计划是基于在小鼠中进行的有据可查的研究，这些研究表明， 交叉调节细胞因子指定Th 1和Th 2的分化 从一个共同的前体淋巴细胞亚群在抗原的时间 呈递，覆盖其他变量的影响，例如抗原 剂量和MHC II类基因型。待研究的慢病毒系统是 萨宁山羊关节炎-脑炎病毒（CAEV）。本实用 评估Th 1对SU的反应的作用的CAEV模型 慢病毒复制和疾病的免疫控制被增强， 初步数据支持以下结论：（1）CAEV感染山羊 至少两个SU应答性CD 4 + T淋巴细胞群， 二分法抗原特异性增殖反应和模式 IFN γ基因表达类似于Th 1和Th 2细胞。(2)主导地位 CAEV SU应答性Th 1细胞的数量与 限制病毒载量和缺乏疾病进展。(3)的程度 CAEV的复制和疾病可能是由差异激活决定的 SU反应性Th 1或Th 2淋巴细胞亚群在或接近 感染因此，这项研究的预期结果将 证明了使用重组细胞因子聚焦 抗原特异性Th淋巴细胞途径，并提供 有机会直接检查Th 1应答在免疫中的作用， 控制持续的慢病毒感染。

This proposal tests the hypothesis that a focused cell mediated immune response to immunization with a purified lentiviral surface (SU) glycoprotein will control virus replication and disease following challenge infection with homologous and heterologous virus. The research plan is to focus antigen specific T helper (Th) 1 lymphocyte responses by enhancing in vivo production of gamma interferon (IFN gamma) at the time of immunization. A vaccinia virus vector and plasmid DNA expressing IFN gamma cDNA will be evaluated to enhance IFN gamma production in vivo. This plan is based on well documented studies in mice demonstrating that crossregulatory cytokines specify the differentiation of Th1 and Th2 lymphocyte subsets from a common precursor at the time of antigen presentation, overriding the effects of other variables such as antigen dosage and MHC class II genotype. The lentiviral system to be studied is caprine arthritis-encephalitis virus (CAEV) in Saanen goats. The utility of the CAEV model for evaluating the role of Th1 responses to SU in immune control of lentivirus replication and disease is enhanced by preliminary data supporting the following: (1) CAEV infected goats have at least two populations of SU responsive CD4+ T lymphocytes with dichotomous antigen specific proliferative responses and patterns of IFNgamma gene expression analogous to Th1 and Th2 cells. (2) Dominance of CAEV SU responsive Th1 cells is specifically associated with restricted virus load and lack of disease progression. (3) The extent of CAEV replication and disease may be determined by differential activation of SU responsive Th1 or Th2 lymphocyte subsets at or near the time of infection. Thus, the anticipated results of this research will demonstrate the feasibility of using recombinant cytokines to focus antigen specific Th lymphocyte pathways in outbred species and provide an opportunity to directly examine the role of Th1 responses in immune control of a persistent lentivirus infection.