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%是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的。在我们基因组中插入逆转录病毒的数量约为40,000个，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，但有些似乎是完整的，有些含有一个或多个病毒基因，这些基因在发育过程中和某些生理或病理条件下表达。关于逆转录病毒表达的控制或这种表达对宿主生理或病理的影响，人们知之甚少。一组被广泛研究的内源性逆转录病毒是那些在小鼠身上引起多嗜性小鼠白血病病毒(MuLV)的病毒。在一些情况下，多向MULV直接与发病机制有关，包括诱导增殖性、免疫性和神经系统疾病。多向性MuLV是由近交系小鼠基因组中存在的外源生态MULV与内源性包膜序列重组而成的。外源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前病毒转录成RNA链，该RNA链与外源MuLV转录本共同包装为异源二聚体病毒RNA。在随后的感染过程中，异源二聚体可以在逆转录过程中进行重组。虽然内源性多嗜性前病毒是转录的，但没有观察到内源性多嗜性病毒在没有重组的情况下复制。在许多情况下，这可能反映了内源性病毒基因组中的点突变或缺失等缺陷，但也可能受到各种限制因子活性的影响。外源性MULV能够在小鼠体内复制的事实表明，它们已经进化出机制来绕过至少一些限制因子的活性，例如小鼠的APOBEC3。因此，外源性逆转录病毒可能通过内源性逆转录病毒的互补和主动复制来促进。我们已经发现，外源病毒感染小鼠会导致完整的内源性前病毒基因序列的感染性转移。这包括有严重缺陷并具有大量缺失的前病毒，以及全长的前病毒。此外，转移的序列被转录并包装成从新感染的细胞释放的病毒粒子。在感染Friend MuLV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普遍。完整内源性逆转录病毒的动员是史无前例的，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与小鼠狼疮性肾炎有关。这种蛋白是由肝细胞分泌的一种急性期蛋白，被认为是内源性异嗜性病毒的产物。然而，由于内源性多嗜性病毒编码的gp70与外源性gp70密切相关，这些病毒可能是血清gp70的额外来源。为了更好地了解血清gp70表达的遗传学基础，我们分析了不同品系小鼠肝脏中异嗜性和多向性gp70 RNA的丰度以及相应的内源性前病毒的基因组组成，包括两种不同的SGP(血清gp70产物)同基因小鼠。这些研究揭示了多变的gp70对血清gp70的显著贡献。此外，给小鼠注射脂多糖，Toll样受体4的配体，选择性地上调不同类别的内源性病毒，表明不同的逆转录病毒gp70在生理和炎症条件下受到不同的调节。

项目成果

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

遗传机制的解剖，涉及与鼠狼疮炎有关的血清逆转录病毒GP70的表达。

• 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