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: 8156819
• 负责人: LEONARD EVANS
• 金额: $ 20.47万
• 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/8156819
• 关键词: Retroviridae Infections; leukemia; nervous system disorder

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. To examine these questions in a less complex system we have extended these studies to examine mixed retrovirus infections of in vitro cell lines. In 2010 our studies revealed that mixed infections of in vitro cell lines with ecotropic and polytropic MuLVs resulted in amplification and pseudotyping characteristics remarkably similar to what we have observed in vivo. In all cases of mixed infections of cell lines with ecotropic MuLVs with polytropic MuLVs the polytropic MuLV genome was extensively pseudotyped within ecotropic virions and the infectious polytropic virus titer was profoundly elevated in co-infected cells. An amphotropic MuLV in mixed infections with a polytropic MuLV yielded similar results. In this case, the polytropic MuLV was pseudotyped within amphotropic virions and the infectious polytropic virus titer elevated. This result indicates that the amplification of the polytropic MuLV in mixed infections is not restricted to combinations of the polytropic virus with its ecotropic parent. The elevation of polytropic MuLV infectivity released from co-infected cells could have resulted from an increase in the level of polytropic genomes released. Alternatively, the observed increase could reflect a much higher specific infectivity of ecotropic or amphotropic virions compared to polytropic virions. We have found in polytropic MuLV mixtures with either ecotropic or amphotropic MuLVs, that much of the increase in polytropic virus titer can be attributed to an increase in the efficiency of packaging and release of the polytropic genome from co-infected cells.

鼠白血病病毒 (MuLV) 在小鼠体内诱发多种疾病，涉及称为多向性 MuLV 的逆转录病毒变体的参与。 这些包括诱导增殖、免疫和神经疾病。 多向性 MuLV 是通过外源共向性 MuLV 与近交小鼠品系基因组中存在的内源包膜序列重组而形成的，从而产生利用独特的细胞表面受体进行感染的病毒。 亲嗜性 MuLV 的感染宿主范围仅限于小鼠；然而，用亲嗜性 MuLV 接种小鼠后产生的重组多向性病毒能够感染许多其他物种以及小鼠。 因此，多向病毒的产生导致具有不同感染特性的病毒的混合逆转录病毒感染。 我们早期的研究强烈表明，宿主中共嗜性和多嗜性 MuLV 的相互作用在促进肿瘤发生中发挥着作用。 最近，我们通过将多向性 MuLV 分离株和亲向性 MuLV 的混合物共同接种给小鼠，研究了体内混合感染中逆转录病毒的相互作用。 与感染混合物中的单个病毒相比，感染特定的逆转录病毒混合物的小鼠表现出显着改变的病理学。 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。 在这两种情况下，共同接种的小鼠中的多向性病毒载量显着增强，而共向性 MuLV 的水平没有变化。 此外，在共同接种的小鼠中，多向性 MuLV 几乎完全被假型化在共向性病毒体中。 有许多可能的机制可以促进多向性 MuLV 的体内深度扩增，包括由于亲向性病毒颗粒内的假型或共感染细胞中多向性病毒可能的反式激活而增强病毒的传播。为了在不太复杂的系统中研究这些问题，我们将这些研究扩展到检查体外细胞系的混合逆转录病毒感染。 2010 年，我们的研究表明，共嗜性和多向性 MuLV 混合感染体外细胞系会导致扩增和假型特征与我们在体内观察到的情况非常相似。 在所有用亲嗜性 MuLV 和多嗜性 MuLV 混合感染细胞系的情况下，多嗜性 MuLV 基因组在亲嗜性病毒粒子内广泛假型化，并且在共感染的细胞中，传染性多嗜性病毒滴度显着升高。 双嗜性 MuLV 与多嗜性 MuLV 混合感染时产生了相似的结果。 在这种情况下，多向性 MuLV 在兼嗜性病毒粒子内被假型化，并且传染性多向性病毒滴度升高。 这一结果表明，多向性MuLV在混合感染中的扩增并不限于多向性病毒与其共向性亲本的组合。 共感染细胞释放的多向 MuLV 感染性升高可能是由于释放的多向基因组水平增加所致。 或者，观察到的增加可能反映出与多向性病毒颗粒相比，共嗜性或兼嗜性病毒颗粒具有更高的特异性感染性。 我们发现，在多向性 MuLV 与共向性或兼嗜性 MuLV 的混合物中，多向性病毒滴度的增加很大程度上可归因于共感染细胞中多向性基因组的包装和释放效率的提高。