Genetic Structure Of Murine Retroviruses

鼠逆转录病毒的遗传结构

• 批准号: 7732432
• 负责人: Leonard Evans
• 金额: $ 75.34万
• 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/7732432
• 关键词: Acute-Phase Proteins; Cells; Class; Condition; Congenic Mice; DNA; Defect; Development; Disease; Elements; Endogenous Retroviruses; Evolution; Friends; Genes; Genetic; Genetic Recombination; Genetic Structures; Genetic Transcription; Genome; Genomics; Germ Cells; Glycoproteins; Goals; Hepatocyte; Human; Inbred Strains Mice; Infection; Inflammatory; Injection of therapeutic agent; Length; Ligands; Lipopolysaccharides; Liver; Lupus Nephritis; Mammals; Modeling; Mouse Strains; Murine leukemia virus; Mus; Numbers; Pathogenesis; Pathologic Processes; Pathology; Physiological; Physiology; Point Mutation; Process; Production; Proteins; Proviruses; RNA; Range; Retroviridae; Reverse Transcription; Role; Serum; Source; Time; Transcript; Viral Genes; Viral Genome; Virion; Virus; base; insight; nervous system disorder; toll-like receptor 4

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. The endogenous retroviral envelope glycoprotein, gp70 is implicated in murine lupus nephritis. This protein is secreted by hepatocytes as an acute phase protein and has been believed to be a product of an endogenous xenotropic virus. However, since endogenous polytropic viruses encode gp70s that are closely related to xenotropic gp70, these viruses can be additional sources of serum gp70. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of xenotropic and polytropic gp70 RNAs in livers and the genomic composition of corresponding endogenous proviruses in various strains of mice, including two different Sgp (serum gp70 production) congenic mice. These studies revealed a significant contribution of polytropic gp70s to serum gp70. Furthermore, injection of mice with lipopolysaccharides, a ligand for the toll-like receptor 4, selectively upregulated different classes of endogenous viruses indicating that that distinct retroviral gp70s are differentially regulated in physiological vs. inflammatory conditions.

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感染的逆转录病毒元素组成。我们的基因组中的逆转录病毒插入约40,000，与我们的DNA编码的基因总数相同。许多内源性逆转录病毒元件有缺陷，但是有些元素似乎完好无损，其中一些包含一个或多个在发育和某些生理或病理状况中表达的病毒基因。关于逆转录病毒表达的控制或这种表达对宿主的生理或病理的影响知之甚少。一组经过广泛研究的内源性逆转录病毒是导致小鼠多恐惧的鼠白血病病毒（MULV）引起的。在多种情况下，多层状MULV已直接与发病机理有关，包括诱导增殖，免疫学和神经系统疾病。通过重组外源性生态MULV形成了多粒子MULV，并具有内源性包膜序列中存在于近交小鼠菌株基因组中。 外源性和内源性逆转录病毒基因组之间的重组需要将完整的内源性病毒转录到与外源性Mulv转录物作为异二酰化病毒体RNA共同包装的RNA链中。 随后感染后，异二聚体可以在逆转录过程中进行重组。 尽管内源性多面体病毒被转录；在没有重组的情况下，内源性多环反应病毒的复制尚未观察到。 在许多情况下，这可能反映了内源性病毒基因组中的点突变或缺失等缺陷，但也可能受到各种限制因素的活性的影响。 外源MULV能够在小鼠中复制的事实表明，它们已经发展出了至少某些限制因素（例如Murine apobec3）的活性的机制。 因此，外源性逆转录病毒可能通过补充，内源性逆转录病毒的主动复制来促进。 我们发现，外源性病毒感染小鼠会导致完全内源性病毒遗传序列的感染性转移。 这包括严重有缺陷且具有大删除和全长的预科病毒的预科病毒。 此外，转移的序列被转录并包装到从新感染的细胞中释放的病毒体中。在与朋友Mulv感染后的早期，完整的内源性逆转录病毒的包装和转移比重组更为普遍。 完整内源性逆转录病毒的动员是前所未有的，可能对内源性逆转录病毒参与疾病过程具有重要意义。 内源性逆转录病毒包膜糖蛋白GP70与鼠狼疮肾炎有关。 该蛋白被肝细胞分泌为急性相蛋白，被认为是内源异种病毒的产物。 但是，由于内源性多粒子病毒编码与异形GP70密切相关的GP70，因此这些病毒可能是血清GP70的其他来源。 为了更好地理解血清GP70表达的遗传基础，我们分析了肝脏中异形和多面体GP70 RNA的丰度，以及各种小鼠中相应内源性病毒的基因组组成，包括两种不同的SGP（血清GP70生产），包括两种不同的SGP（血清GP70生产）。 这些研究揭示了多面体GP70对血清GP70的显着贡献。 此外，用脂多糖注射小鼠，一种类似Toll样受体4的配体，有选择地上调不同类别的内源性病毒，表明在生理和炎症条件下，不同的逆转录病毒GP70在生理中受到差异性调节。

项目成果

Dissection of genetic mechanisms governing the expression of serum retroviral gp70 implicated in murine lupus nephritis.

• DOI: 10.4049/jimmunol.181.4.2846
• 发表时间: 2008-08-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Baudino, Lucie;Yoshinobu, Kumiko;Morito, Naoki;Kikuchi, Shuichi;Fossati-Jimack, Liliane;Morley, Bernard J.;Vyse, Timothy J.;Hirose, Sachiko;Jorgensen, Trine N.;Tucker, Rebecca M.;Roark, Christina L.;Kotzin, Brian L.;Evans, Leonard H.;Izui, Shozo
• 通讯作者: Izui, Shozo

Retroviral vectors bearing IgG-binding motifs for antibody-mediated targeting of vascular endothelial growth factor receptors.

带有 IgG 结合基序的逆转录病毒载体，用于抗体介导的血管内皮生长因子受体靶向。

• DOI: 10.3892/ijmm.8.4.335
• 发表时间: 2001
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: Masood,R;Gordon,EM;Whitley,MD;Wu,BW;Cannon,P;Evans,L;Anderson,WF;Gill,P;Hall,FL
• 通讯作者: Hall,FL