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基因改变。 通过点突变或重组产生的变体 可能表现出不同的感染和致病特性。这个 这些变异体的产生及其在致病性中的作用是一个 这个项目的主要关注点。感染生态型小鼠的小鼠 白血病病毒(MuLV)与一种非常 一组密切相关的内源性逆转录病毒env基因序列 以产生多嗜性病毒。多嗜性病毒利用不同的 细胞受体，并表现出与亲本不同的宿主范围 生态型MuLV，并被牵涉到诱导 增殖性疾病的数量。近交系小鼠品系中含有 它们的基因组中有30到40个内源序列 与多嗜性MULV的env基因同源。我们有 确定至少有几个这样的序列参与 然而，重组逆转录病毒的产生，它们的参与 显然不是随机的。我们最近描述了两个主要的 多变MULV的抗原亚类 与不同的内源序列重组。不同 接种生态型MULV后，产量一直明显不同 抗原亚类的比例。我们目前的目标之一是 以阐明这种选择性的基础。为此，我们定义了 编码核衣壳基因的一小段区域和部分 强烈影响多角体类型的蛋白酶基因 在受感染的小鼠身上产生的MULV。第二个目标是 这个项目是为了阐明病毒相互作用对 混合逆转录病毒的病毒传播和病理动态 感染，如因基因突变而产生的感染 变种。伪分型和病毒干扰等现象 是混合病毒相互作用的后果，但潜在的 这些交互作用赋予组件协同效应 对感染的了解还不是很清楚。我们对混合病毒的初步研究 被认为是生态型和多变性病毒相互作用的感染 在Moloney(M)MuLV.这部作品 提出了一种促进肿瘤发生的分步机制 伪分型和干扰。最近我们的努力是 针对由以下原因引起的混合逆转录病毒感染的影响 生态型和多嗜型MuLV分离株的共接种。我们有 在两种共同接种的病毒之间发现了惊人的协同作用， 这会导致一种迅速致命的神经系统疾病 感染后10至15天。多变MuLV的能级 与小鼠相比，联合接种小鼠的感染率显著升高。 单独感染多嗜性弱毒病毒。中的此增强功能 复制很可能是几乎完全的伪分型的结果 在整个生态型病毒粒子中的多嗜性小病毒基因组 感染的过程。多变基因组广泛存在于 在感染后病毒传播的最早时间出现假型 在宿主中是最小的。考虑到伪类型化只能 发生在这两种病毒感染的细胞中，这一观察表明 两种接种的病毒最初感染的是相同的小 细胞数量。对感染水平的检查和对 病毒最早出现时的伪分型程度 在联合接种的小鼠中检测到，显示出聚集性感染 小种群(1%)的生态型和多带型MULV 外周血细胞。FACS的分析表明，这一群体 单核/巨噬细胞谱系。