Genetic Structure Of Murine Retroviruses

鼠逆转录病毒的遗传结构

• 批准号: 7592128
• 负责人: Leonard Evans
• 金额: $ 94.8万
• 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/7592128
• 关键词: Cells; Condition; DNA; Defect; Development; Disease; Elements; Endogenous Retroviruses; Evolution; Friends; Genes; Genetic; Genetic Recombination; Genetic Structures; Genetic Transcription; Genome; Germ Cells; Goals; Human; Inbred Strains Mice; Infection; Length; Mammals; Modeling; Murine leukemia virus; Mus; Numbers; Pathogenesis; Pathologic Processes; Pathology; Physiological; Physiology; Point Mutation; Process; Proviruses; RNA; Range; Retroviridae; Reverse Transcription; Role; Time; Transcript; Viral Genes; Viral Genome; Virion; Virus; insight; nervous system disorder

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. Recombination between the exogenous and endogenous retrovirus genomes requires transcription of a complete endogenous provirus to an RNA strand which is co-packaged with an exogenous MuLV transcript as a heterodimeric virion RNA. Upon subsequent infection, the heterodimer can undergo recombination during reverse transcription. Although the endogenous polytropic proviruses are transcribed; replication of the endogenous polytropic viruses in the absence of recombination has not been observed. This may, in many cases, reflect defects such as point mutations or deletions in the endogenous viral genome but may also be influenced by the activity of various restriction factors. The fact that exogenous MuLVs are capable of replicating in mice indicates that they have evolved mechanisms to circumvent the activity of at least some of the restriction factors such as the murine APOBEC3. Thus, exogenous retroviruses might facilitate through complementation, active replication of endogenous retroviruses. We have found that infection of mice by an exogenous virus results in the infectious transfer of complete endogenous proviral genetic sequences. This includes proviruses which are severely defective and possess large deletions as well as proviruses that are full-length. Furthermore, the transferred sequences are transcribed and packaged into virions released from the newly infected cells. 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约有8%由在进化过程中通过生殖系细胞感染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，与我们DNA编码的基因总数相同。许多内源性逆转录病毒元件是有缺陷的，然而一些似乎是完整的，并且一些含有在发育和某些生理或病理条件期间表达的一个或多个病毒基因。关于逆转录病毒表达的控制或这种表达对宿主的生理或病理的影响知之甚少。一组广泛研究的内源性逆转录病毒是在小鼠中产生嗜多性鼠白血病病毒（MuLV）的那些。在一些情况下，多变性MuLV直接参与发病机制，包括诱导增殖性、免疫性和神经系统疾病。通过外源亲嗜性MuLV与存在于近交系小鼠品系基因组中的内源性包膜序列重组形成多嗜性MuLV。 外源性和内源性逆转录病毒基因组之间的分离需要将完整的内源性前病毒转录成RNA链，该RNA链与外源性MuLV转录物共包装为异二聚体病毒体RNA。 在随后的感染后，异二聚体可以在逆转录期间经历重组。 虽然内源性多变性前病毒被转录，但尚未观察到内源性多变性病毒在不存在重组的情况下复制。 在许多情况下，这可能反映了内源性病毒基因组中的缺陷，如点突变或缺失，但也可能受到各种限制因子活性的影响。 外源性MuLV能够在小鼠中复制的事实表明，它们已经进化出了规避至少一些限制因子（如鼠APOBEC3）活性的机制。 因此，外源性逆转录病毒可能通过互补促进内源性逆转录病毒的主动复制。 我们已经发现，外源性病毒感染小鼠导致完整内源性前病毒基因序列的感染性转移。 这包括严重缺陷并具有大缺失的前病毒以及全长前病毒。 此外，转移的序列被转录并包装到从新感染的细胞释放的病毒体中。在Friend MuLV感染后的早期，完整内源性逆转录病毒的包装和转移比重组更为普遍。 完整的内源性逆转录病毒的动员是前所未有的，并可能有重要的影响，内源性逆转录病毒参与疾病过程。