MECHANISMS OF THE H-2 EFFECT ON VIRAL LEUKEMOGENESIS

对病原体如逆转录病毒的抗性可能是遗传的 或后天获得。 我们建议研究小鼠红白血病 小鼠白血病病毒（MuLV）复合Friend株（FV） 其中可以观察到两种类型的抗性，并且似乎取决于 部分类似的潜在免疫机制，涉及主要的 小鼠的组织相容性复合物，H-2。 我们的发现可能会作为 研究艾滋病类似方面的模型。 在H-2的D区域中不同的某些基因型的小鼠 显示出明显不同的遗传易感性或抗性水平， FV，但这种可能的免疫效应的机制从来没有 被明确证明。 我们会特别研究 H-2单倍型赋予FV抗性的机制， 纯合子小鼠在同类杂合子中不再如此。 我们提出 这种效应的研究将精确地识别D区基因， 通过使用重组和突变的H-2基因作图， 单倍型，通过分析转染细胞的相关菌株， 转基因小鼠的研究和基于基因的已知特性的研究 在这个地区的地图。 我们还将研究细胞的各个方面， 对FV的免疫应答在获得性免疫缺陷的发展中似乎至关重要， 抵抗病毒。 我们将鉴定特定的氨基酸序列 在病毒gag/pol和env基因中，与H-2D区基因一起 产物，构成了FV特异性细胞毒性T细胞所见的结构。 淋巴细胞（CTL）。 我们将开发病毒相关的RNA结构， 有复制缺陷和非致病性，但富含 CTL识别的表位决定簇， 鉴定 我们将这些表位富集的构建体包装在FV中， 这些粒子应该能够产生强烈的免疫反应 通过刺激II类H-22基因限制性 抗原呈递途径和刺激I类H-22 基因限制性内源途径。 这些药物的功效， 将确定候选疫苗。

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.