MECHANISMS OF THE H-2 EFFECT ON VIRAL LEUKEMOGENESIS

对逆转录病毒等病原体的抵抗力可能是遗传的 或者是后天收购。我们建议对小鼠的红白血病疾病进行研究 小鼠白血病病毒复合Friend株(Fv)的诱导 在这种情况下，可以观察到这两种类型的抗性，并似乎取决于 部分类似的潜在免疫学机制涉及主要 小鼠组织相容性复合体H-2。我们的发现可以作为 研究艾滋病毒疾病相似方面的模型。 H-2 D区某些不同基因类型的小鼠 表现出明显不同的遗传易感性或抗药性水平 FV，但这种可能的免疫效应的机制从未 已经得到了确凿的证明。我们会特别研究 H-2单倍型对赤霉病的抗性机制 纯合子小鼠在同源杂合子中不再这样做。我们建议 对这一效应的研究将准确地识别D区基因 通过使用重组和突变H-2的遗传图谱所涉及的 单倍型，通过对相关品系的转基因细胞和 转基因小鼠和基于已知基因特性的研究 这一地区的地图绘制。我们还将研究细胞的各个方面 对FV的免疫反应似乎在获得性疾病的发展中起关键作用 对病毒的抵抗力。我们将识别特定的氨基酸序列 在病毒的gag/pol和env基因中，与H-2D区基因一起 产物，构成Fv特异性细胞毒T细胞的结构 淋巴细胞(CTL)。我们将开发与病毒相关的RNA结构，这些结构 对复制有缺陷，无致病性，但对 我们将拥有的CTL识别表位的决定因素 已确认身份。我们将把这些富含表位的构建体包装在FV中 这些颗粒应该能够产生强烈的免疫反应 在宿主小鼠中既受第II类H-22基因的刺激限制 抗原提呈途径和刺激I类H-22的途径 基因受限的内源途径。这些药物的疗效是 候选疫苗将被确定。

Resistance to pathogenic agents such as retroviruses may be genetic or acquired. We propose studies of the erythroleukemic disease of mice induced by the complex Friend strain (FV) of mouse leukemia virus (MuLV) in which both types of resistance can be observed and appear to depend in part on similar underlying immunologic mechanisms involving the major histocompatibility complex of the mouse, H-2. Our findings may serve as models for the study of analogous aspects of HIV disease. Mice of certain genotypes that differ in the D region of H-2 show markedly different levels of genetic susceptibility or resistance to FV, but the mechanism of this presumably immunologic effect has never been definitively demonstrated. In particular, we will study the mechanisms whereby H-2 haplotypes that confer resistance to FV in homozygous mice no longer do so in congenic heterozygotes. We propose studies of this effect that will precisely identify the D region genes involved by the use of genetic mapping with recombinant and mutant H-2 haplotypes, by the analysis of relevant strains of transfected cells and of transgenic mice and by studies based on the known properties of genes mapping in this region. We will also study aspects of the cellular immune response to FV that appear critical in the development of acquired resistance to the virus. We will identify specific amino acid sequences in the viral gag/pol and env genes that, together with H-2D region gene products, constitute the structures seen by FV-specific cytotoxic T lymphocytes (CTL). We will develop virus-related RNA constructs that are defective for replication and nonpathogenic but enriched for the determinants of the epitopes recognized by CTL that we will have identified. We will package these epitope-enriched constructs in FV particles which should then be able to generate a strong immune response in host mice both by stimulation of the class II H-22 gene-restricted pathway for antigen presentation and by stimulation of the class I H-22 gene-restricted endogenous pathway. The efficacy of these agents as candidate vaccines will be determined.