IMMUNE CONTROL OF CAE LENTIVIRUS

这一提议检验了一种假设，即聚焦的细胞介导的免疫 纯化的慢病毒表面(SU)免疫应答 糖蛋白将控制病毒复制和后续疾病 挑战同源和异源病毒的感染。这项研究 计划集中抗原特异性T辅助细胞(Th)1淋巴细胞反应 通过增加体内产生的干扰素(干扰素)在 免疫时间。痘苗病毒载体及表达载体DNA的构建 将对干扰素-γ基因在体内促进干扰素-γ的产生进行评估。 这一计划是基于对小鼠进行的有充分记录的研究，表明 交叉调节细胞因子指定Th1和Th2的分化 抗原时来自共同前体的淋巴细胞亚群 呈现，覆盖其他变量的影响，如抗原 剂量和MHC II类基因。要研究的慢病毒系统是 萨能山羊的山羊关节炎脑炎病毒(CAEV)。该实用程序 用CAEV模型评价Th1应答对SU的作用 通过以下方式增强对慢病毒复制和疾病的免疫控制 初步数据支持如下：(1)感染CAEV的山羊有 至少两组SU反应性CD4T淋巴细胞 二分性抗原特异性增殖反应和模式 干扰素-γ基因表达类似于Th1和Th2细胞。(2)优势 CAEV SU反应性Th1细胞中 病毒载量受到限制，疾病没有进展。(3)涉及的范围 CAEV复制和疾病可通过差异激活来确定 SU反应性Th1/Th2淋巴细胞亚群在发病前后的变化 感染。因此，这项研究的预期结果将 论证使用重组细胞因子聚焦的可行性 近交系物种中抗原特异的Th淋巴细胞途径和提供 直接研究Th1反应在免疫中的作用的机会 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.