Genetic Structure Of Murine Retroviruses

鼠逆转录病毒的遗传结构

• 批准号: 7299909
• 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/7299909
• 关键词: Genetic; Structure; Murine; Retroviruses

Approximately 8% of the genomes of mammals, including humans and mice, are comprised of retroviral elements acquired by infection of germ line cells during the course of evolution. Retroviral insertions in our genome number about 40,000 and are in the same range as the total number of genes encoded by our DNA. Many endogenous retrovirus elements are defective, however some appear to be intact, and several contain one or more viral genes that are expressed during development and certain physiological or pathological conditions. Little is known about the control of retrovirus expression or the influence of such expression on the physiology or pathology of the host. An extensively investigated group of endogenous retroviruses are those giving rise to polytropic murine leukemia viruses (MuLVs) in mice. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. Polytropic MuLVs are formed by recombination of exogenous ecotropic MuLVs with endogenous envelope sequences present in the genomes of inbred mouse strains and their generation results in a mixed retrovirus infection. We have investigated the interactions of retroviruses in mixed infections in vivo by co-inoculation of mice with polytropic and ecotropic MuLVs and observed remarkable alterations in the types and tempo of disease induced by different mixtures of viruses. These included a highly significant delay in the induction of proliferative disease with one polytropic MuLV and a profound synergistic effect resulting in the abrupt development of a neurological disease with another polytropic isolate. In the first case the delay in disease induction correlated with in vivo retroviral interference resulting in the suppression the generation of new polytropic MuLVs normally observed after infection with the exogenous ecotropic MuLV. The rapid development of neurological disease were accompanied by extensive pseudotyping of the polytropic MuLV genome within ecotropic virions and a striking elevation of polytropic MuLV infection and replication in co-inoculated mice. Another aspect of our studies involves the characterization of the family of endogenous retroviruses that participate in recombination to yield polytropic MuLVs. Structural studies of these endogenous viruses suggest that they have undergone recent periods of active replication. We have found that mice infected with exogenous retroviruses release infectious virus particles containing RNA sequences corresponding to complete transcripts of the endogenous proviruses. At early times after infection with the Friend MuLV, packaging and transfer of intact endogenous retroviruses is much more prevalent than recombination. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes.

包括人类和小鼠在内的哺乳动物的基因组中大约 8% 由在进化过程中通过感染生殖系细胞获得的逆转录病毒元件组成。我们基因组中的逆转录病毒插入数量约为 40,000 个，与我们 DNA 编码的基因总数处于同一范围。许多内源性逆转录病毒元件是有缺陷的，但有些似乎是完整的，并且有一些含有一种或多种在发育和某些生理或病理条件下表达的病毒基因。关于逆转录病毒表达的控制或这种表达对宿主生理学或病理学的影响知之甚少。一组经过广泛研究的内源性逆转录病毒是在小鼠体内产生多向性鼠白血病病毒（MuLV）的病毒。在一些情况下，多向性 MuLV 直接参与发病机制，包括诱导增殖、免疫和神经系统疾病。多向性 MuLV 是通过外源共向性 MuLV 与近交系小鼠品系基因组中存在的内源性包膜序列重组而形成的，它们的产生导致混合逆转录病毒感染。我们通过给小鼠同时接种多向性和共向性 MuLV，研究了逆转录病毒在体内混合感染中的相互作用，并观察到不同病毒混合物引起的疾病类型和速度的显着变化。其中包括一种多变性 MuLV 诱导增殖性疾病的高度显着延迟，以及与另一种多变性分离株产生的深刻协同效应，导致神经系统疾病突然发展。在第一种情况下，疾病诱导的延迟与体内逆转录病毒干扰相关，导致抑制通常在感染外源亲嗜性 MuLV 后观察到的新多向性 MuLV 的产生。神经系统疾病的快速发展伴随着亲嗜性病毒颗粒内多向性 MuLV 基因组的广泛假型化，以及联合接种小鼠中多向性 MuLV 感染和复制的显着升高。 我们研究的另一个方面涉及内源性逆转录病毒家族的特征，该家族参与重组以产生多向性 MuLV。这些内源病毒的结构研究表明它们最近经历了活跃复制期。我们发现感染外源性逆转录病毒的小鼠会释放出感染性病毒颗粒，其中含有与内源性原病毒的完整转录物相对应的RNA序列。在感染 Friend MuLV 后的早期，完整内源性逆转录病毒的包装和转移比重组更为普遍。完整内源逆转录病毒的动员是前所未有的，可能对内源逆转录病毒参与疾病过程具有重要意义。