GENETIC STRUCTURE OF MURINE RETROVIRUSES

鼠逆转录病毒的遗传结构

• 批准号: 6098900
• 负责人: Leonard Evans
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6098900
• 关键词: gene induction /repression; laboratory mouse; murine leukemia virus; neoplasm /cancer genetics; protooncogene; viral carcinogenesis; viral leukemia; virus genetics

Retroviruses frequently undergo genetic alteration by point mutation or by recombination to generate variants which may exhibit different infectious and pathogenic properties. The generation of these variants and their role in pathogenicity is a major focus of this project. Mice infected with ecotropic murine leukemia viruses (MuLV) recombine with members of a very closely related group of endogenous retroviral env-gene sequences to generate polytropic viruses. Polytropic viruses utilize a different cellular receptor and exhibit a host range distinct from the parental ecotropic MuLV and have been implicated in the induction of a number of proliferative diseases. Inbred mouse strains contain in their genomes 30 to 40 endogenous sequences that are closely homologous to the env genes of polytropic MuLVs. We have determined that at least several of these sequences participate in the generation of recombinant retroviruses, however, their participation is clearly non-random. We have recently described two major antigenic subclasses of polytropic MuLVs which correspond to recombination with distinct endogenous sequences. Different inoculated ecotropic MuLVs consistently yield distinctly different ratios of the antigenic subclasses. One of our current objectives is to elucidate the basis of this selectivity. To this end we have defined a small region encoding the nucleocapsid gene and a portion of the protease gene which strongly influences the types of polytropic MuLVs that are generated in infected mice. A second objective of this project is to elucidate the effects of viral interactions on the dynamics of virus spread and pathology in mixed retrovirus infections such as that generated by the emergence of genetic variants. Phenomena such as pseudotyping and viral interference are consequences of mixed viral interactions, but the potential for these interactions to confer synergism on the components of the infection is not well understood. Our initial studies of mixed virus infections considered ecotropic and polytropic viral interactions during leukemogenesis by Moloney (M) MuLV. This work suggested a stepwise mechanism of oncogenesis facilitated by pseudotyping and interference. Recently our efforts have been directed at the effects of mixed retrovirus infections generated by co-inoculation of ecotropic and polytropic MuLV isolates. We have found a striking synergism between the two co-inoculated viruses, which results in a rapidly fatal neurological disease occurring within 10 to 15 days after infection. The level of the polytropic MuLV infection is highly elevated in co-inoculated mice compared to mice infected with the polytropic MuLV alone. This enhancement in replication is likely the result of nearly complete pseudotyping of the polytropic MuLV genome within ecotropic virions throughout the course of infection. Polytropic genomes are extensively pseudotyped at the earliest times after infection when virus spread in the host is minimal. Considering that pseudotyping can only occur in cells infected by both viruses, this observation indicates that both of the inoculated viruses initially infect the same small population of cells. Examination of the level of infection and the degree of pseudotyping at the earliest times that virus can be detected in co-inoculated mice, revealed a converging infection of the ecotropic and polytropic MuLVs in a small population (<1%) of periferal blood cells. FACS analyses suggest that this population is of the monocyte/macrophage lineage.

逆转录病毒经常发生遗传改变 按点突变或通过重组产生变体，这些变体 可能表现出不同的感染和致病性能。这 这些变体的产生及其在致病性中的作用是 该项目的主要重点。感染生态鼠的小鼠 白血病病毒（MULV）与一个非常非常的成员重组 紧密相关的内源性逆转录病毒环境序列 生成多潮流病毒。多潮流病毒利用了不同的 细胞受体并表现出与父母不同的宿主范围 生态MULV，并与诱导有关 增生性疾病的数量。近交小鼠菌株包含 它们的基因组30至40个内源序列 与多变态MULV的ENV基因同源。我们有 确定其中至少几个序列参与了 但是，重组逆转录病毒的产生 显然是非随机的。我们最近描述了两个主要 多变态MULV的抗原亚类，对应于 重组具有不同的内源序列。不同的 接种的生态MULV始终产生明显不同 抗原亚类的比率。我们目前的目标之一是 阐明这种选择性的基础。为此，我们定义了 一个编码核蛋白基因和一部分的小区域 蛋白酶基因强烈影响多面年的类型 在感染小鼠中产生的MULV。第二个目标 该项目是为了阐明病毒相互作用对 混合逆转录病毒中病毒扩散和病理的动力学 诸如遗传出现产生的感染 变体。诸如假型和病毒干扰等现象 是混合病毒相互作用的后果，但潜力 这些相互作用以赋予协同作用 感染不太了解。我们对混合病毒的初步研究 感染被认为是生态和多粒细胞病毒相互作用 在Moloney（M）Mulv的白血病发生期间。这项工作 提出了促进的逐步机理 假型和干扰。最近我们的努力一直在 针对由混合逆转录病毒感染产生的影响 生态和多趋于MULV分离株的共同接种。我们有 发现两个共同接种的病毒之间存在惊人的协同作用， 这导致发生迅速致命的神经系统疾病 感染后10至15天。多层次MULV的水平 与小鼠相比 单独感染多粒子MULV。这种增强 复制可能是几乎完整的假型的结果 整个生态病毒体内的多粒细胞基因组 感染过程。多面基因组广泛 病毒传播后最早在感染后的最早进行假型 在主机中很小。考虑到假型只能 发生在两种病毒感染的细胞中，该观察结果表明 两种接种病毒最初都会感染相同的小病毒 细胞种群。检查感染水平和 在病毒最早的时候，假型的程度 在共同接种的小鼠中检测到，发现感染的感染 少数人口（<1％） perifer膜血细胞。 FACS分析表明该人群是 单核细胞/巨噬细胞谱系。