Influence of Mixed Retrovirus Infections on Leukemia and Neurological disease

逆转录病毒混合感染对白血病和神经系统疾病的影响

• 批准号: 7964217
• 负责人: LEONARD EVANS
• 金额: $ 38.03万
• 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/7964217
• 关键词: Cell Line; Cell Surface Receptors; Cells; Characteristics; Complex; Development; Disease; Exhibits; Generations; Genetic; Genetic Recombination; Genome; Goals; In Vitro; Inbred Strains Mice; Individual; Infection; Murine leukemia virus; Mus; Mutation; Pathologic Processes; Pathology; Play; Point Mutation; Property; Recombinants; Retroviridae; Retroviridae Infections; Role; System; Transactivation; Variant; Viral load measurement; Virion; Virus; in vivo; leukemia; nervous system disorder; tumorigenesis

The induction of many diseases in mice by murine leukemia viruses (MuLVs), involves the participation of variant retroviruses termed polytropic MuLVs. These include 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 resulting in viruses which utilize a distinct cell-surface receptor for infection. The infectious host range of ecotropic MuLVs is limited to mice; however the recombinant polytropic viruses generated after inoculation of mice with ecotropic MuLVs are capable of infecting a number of other species as well as mice. Thus, the generation of polytropic viruses results in a mixed retrovirus infection of viruses with different infectious properties. Our earlier studies strongly suggest that the interactions of ecotropic and polytropic MuLVs in the host play a role in facilitating oncogenesis. More recently we have investigated the interactions of retroviruses in mixed infections in vivo by co-inoculation of mice with mixtures of polytropic MuLV isolates and ecotropic MuLVs. Mice infected with defined mixtures of retroviruses exhibit dramatically altered pathology compared to infection with the individual viruses of the mixture. 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 both instances the polytropic virus load in the co-inoculated mice was markedly enhanced while the level of the ecotropic MuLV was unchanged. Furthermore, the polytropic MuLV was nearly completely pseudotyped within ecotropic virions in co-inoculated mice. There are a number of possible mechanisms which could facilitate the profound in vivo amplification of the polytropic MuLVs including enhanced spread of the virus due to pseudotyping within ecotropic virions or possibly transactivation of the polytropic virus in co-infected cells. In order to study this phenomenon in a less complex setting, we are currently examining mixed retrovirus infections utilizing in vitro cell lines. We have found that mixed infections of in vitro cell lines with ecotropic and polytropic MuLVs results in amplification and pseudotyping characteristics remarkably similar to what we have observed in vivo. Notably, the polytropic MuLV genome is extensively pseudotyped within ecotropic virions and the infectious polytropic virus titer is profoundly elevated in co-infected cells. This observation could have resulted from an increase in the level of polytropic genomes released from the cells. Alternatively, the observed increase could reflect a much higher specific infectivity of ecotropic virions compared to polytropic virions. Further studies strongly suggest that the increase in polytropic virus titer is not due to differences in specific infectivity, but rather to an increase in the efficiency of packaging and release of the polytropic genome in co-infected cells. .

小鼠白血病病毒（mulv）在小鼠中诱导许多疾病，涉及被称为多性mulv的变异逆转录病毒的参与。这些包括诱发增殖性、免疫和神经紊乱。多嗜性mulv是由外源性生态嗜性mulv与近交系小鼠基因组中存在的内源性包膜序列重组形成的，从而产生利用不同细胞表面受体进行感染的病毒。嗜生态mulv的感染宿主范围仅限于小鼠；然而，用嗜生态mulv接种小鼠后产生的重组多性病毒不仅能感染小鼠，还能感染许多其他物种。因此，多性病毒的产生导致具有不同感染性的病毒的混合逆转录病毒感染。我们早期的研究有力地表明，宿主体内嗜生态和多性mulv的相互作用在促进肿瘤发生中起作用。最近，我们研究了逆转录病毒在体内混合感染中的相互作用，通过共接种小鼠与多嗜性MuLV分离株和生态嗜性MuLV的混合物。与感染特定的逆转录病毒混合物的单个病毒相比，感染特定逆转录病毒混合物的小鼠表现出显著改变的病理。其中包括一种多性MuLV诱导增殖性疾病的显著延迟，以及另一种多性分离株的深刻协同效应导致神经系统疾病的突然发展。在两种情况下，共接种小鼠的多嗜性病毒载量均显著增加，而生态嗜性MuLV水平不变。此外，在共接种的小鼠中，多性MuLV在生态型病毒粒子中几乎完全假型化。有许多可能的机制可以促进多性mulv在体内的深度扩增，包括由于生态病毒粒子内的假分型或可能的多性病毒在共感染细胞中的反激活而增强病毒的传播。为了在一个不太复杂的环境中研究这一现象，我们目前正在利用体外细胞系研究混合逆转录病毒感染。我们发现，在体外细胞系中，嗜生态型和多性型mulv的混合感染导致扩增和假分型特征与我们在体内观察到的非常相似。值得注意的是，多嗜性MuLV基因组在生态病毒粒子中广泛假型化，并且感染性多嗜性病毒滴度在共感染细胞中显著升高。这一观察结果可能是由于从细胞中释放的多性基因组水平的增加。或者，观察到的增加可能反映了与多嗜性病毒粒子相比，生态病毒粒子具有更高的特异性感染性。进一步的研究有力地表明，多性性病毒滴度的增加不是由于特异性感染性的差异，而是由于多性性基因组在共感染细胞中的包装和释放效率的提高。