Influence of Mixed Retrovirus Infections on Leukemia and Neurological disease

小鼠白血病病毒（MuLV）在小鼠中的许多疾病的诱导涉及称为多嗜性MuLV的变体逆转录病毒的参与。 这些包括诱导增殖、免疫和神经系统疾病。 多嗜性MuLV是通过外源性嗜亲性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而形成的，从而产生利用不同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效性病毒能够感染许多其他物种以及小鼠。 因此，嗜多性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，亲嗜性和多嗜性MuLV在宿主中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，通过共接种小鼠与嗜多性MuLV分离株和嗜亲性MuLV的混合物。 与用混合物中的单个病毒感染相比，用确定的逆转录病毒混合物感染的小鼠表现出显著改变的病理学。 这些包括一种多变性MuLV诱导增殖性疾病的高度显著延迟，以及另一种多变性分离株导致神经系统疾病突然发展的显著协同效应。 在这两种情况下，共接种小鼠中的嗜多性病毒载量显著增加，而嗜亲性MuLV水平不变。 此外，在共接种小鼠中，嗜亲性MuLV在嗜亲性病毒粒子内几乎完全假型化。 存在许多可能的机制，其可以促进多变性MuLV的深度体内扩增，包括由于嗜亲性病毒粒子内的假型化或共感染细胞中多变性病毒的可能反式激活而增强的病毒传播。为了在一个不太复杂的系统中研究这些问题，我们将这些研究扩展到研究体外细胞系的混合逆转录病毒感染。 在2011年，我们扩展了早期的研究，表明用亲嗜性和多嗜性MuLV混合感染体外细胞系导致扩增和假型特征与我们在体内观察到的非常相似。 在嗜亲性MuLV与嗜多性MuLV混合感染细胞系的所有情况下，嗜多性MuLV基因组在嗜亲性病毒粒子内广泛假型化，并且感染性嗜多性病毒滴度在共感染细胞中显著升高。 嗜中性MuLV与嗜多性MuLV混合感染产生了类似的结果。 在这种情况下，嗜多性MuLV在嗜多性病毒粒子内假型化，感染性嗜多性病毒滴度升高。 该结果表明，混合感染中的嗜多性MuLV的扩增不限于嗜多性病毒与其亲嗜性亲本的组合。 从共感染细胞释放的多变性MuLV感染性的升高可能是由于释放的多变性基因组水平增加所致。 或者，观察到的增加可能反映了嗜亲性或嗜亲性病毒粒子比嗜多性病毒粒子高得多的特异性感染性。 我们已经发现，在具有嗜亲性或嗜亲性MuLV的多变性MuLV混合物中，多变性病毒滴度的大部分增加可归因于包装效率的增加和多变性基因组从共感染细胞中的释放。 利用释放不同水平的嗜性病毒的克隆细胞系的研究表明，在这些细胞与嗜性病毒共感染后，这些细胞系中的每一个都可以被诱导释放类似的高水平的嗜性病毒。 这些结果进一步表明，共感染亲嗜性病毒有利于包装和释放的多变基因组。

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 2011 we have extended earlier studies indicating that 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. Studies utilizing clonal cell lines releasing different levels of polytropic viruses indicated that each of these lines could be induced to release similar high levels of polytropic virus upon co-infection of these cells with an ecotropic virus. These results further suggest that co-infection with an ecotropic virus facilitates the packaging and release of the polytropic genome.