GENETIC STRUCTURE OF MURINE RETROVIRUSES

视网膜病毒的基因改变已被记录在案 慢病毒，如EIAV和艾滋病病毒，以及 小鼠白血病病毒(MuLV)。生态型MuLV经历了 与小鼠基因序列重组产生 称为多嗜性或水貂细胞病灶形成的重组病毒 (Mcf)病毒，经常被牵连为 与癌变有关的近端物质。一个 这个项目的主要目标是描述重组的 并确定它们在疾病诱导中的作用。初步研究 证明了导致不同类型的生态型病毒 白血病(即红白血病与淋巴细胞性白血病) 与不同的小鼠基因重组产生MCF病毒。 我们使用一种新的逆转录病毒检测方法将这些研究扩展到 定义新的主要重组病毒群体，这些重组病毒 用常规化验无法检测到。新的重组体 在红白血病诱导过程中分离到的菌株显示出明显的 不同的感染特性与 诱导淋巴细胞性白血病，在两个病例中，表现为 绝大多数的重组病毒都存在。 生态型组织特异性复制的进一步研究 病毒表明复制的位置由 病毒的多个序列，并诱导白血病 需要在致癌靶组织中进行高水平的复制 只是短暂的，感染后的早期。 AKR小鼠表现出高水平的自发性白血病和 在紧随其后的致癌重组病毒 白血病的最早发病率。中产生的重组子 AKR小鼠是通过逐步重组机制产生的 这一点还没有完全被理解。我们已经确定和研究了 一种新型病毒在AKR小鼠体内的结构和表达 似乎在这个步骤中起到了重组中间体的作用 进程。我们的发现使我们能够得出一个详细的 致癌重组子的生成模型。

Genetic alterations of retgroviruses have been documented with lentiviruses such as EIAV and the AIDS virus, as well as with murine leukemia viruses (MuLVs). Ecotropic MuLVs undergo recombination with gene sequences of the mouse to generate recombinant viruses termed polytropic or mink cell focus-forming (MCF) viruses, which have frequently been implicated as the proximal agents involved in transformation to malignancy. A major goal of this project is to characterize the recombinant MuLVs and to define their role in disease induction. Initial studies demonstrated that ecotropic viruses which induce distinct types of leukemias (i.e., erythroleukemia vs. lymphocytic leukemia) recombine with distinct mouse genes to generate MCF viruses. We have extended these studies using a novel retrovirus assay to define new major populations of recombinant viruses which were undetected using conventional assays. The new recombinants isolated during erythroleukemia induction exhibited distinctly different infectious properties than those isolated during lymphocytic leukemia induction and, in both cases, represented the overwhelming majority of recombinant viruses present. Additional studies on tissue-specific replication of ecotropic viruses indicated that the site of replication is controlled by multiple sequences of the viruses, and that leukemia induction requires a high level of replication in the oncogenic target tissue only transiently, early after infection. AKR mice exhibit a high level of spontaneous leukemia and express oncogenic recombinant viruses immediately preceding the earliest incidence of leukemia. The recombinants generated in AKR mice are derived by a stepwise recombination mechanism which is not fully understood. We have identified and studied the structure and expression of a new virus in AKR mice which appears to serve as a recombination intermediate in this stepwise process. Our findings have enabled us to arrive at a detailed model for the generation of the oncogenic recombinants.