Influence of Mixed Retrovirus Infections on Leukemia and Neurological disease

小鼠白血病病毒(MULV)引起小鼠多种疾病，涉及到称为多嗜性MULV的逆转录病毒的参与。这包括导致增殖性、免疫性和神经性疾病。多向性MuLV是近交系小鼠基因组中存在的外源性生态MULV与内源性包膜序列重组形成的，导致病毒利用不同的细胞表面受体进行感染。生态型MuLV的感染宿主范围仅限于小鼠；然而，用生态型MuLV接种小鼠后产生的重组多角体病毒能够感染许多其他物种以及小鼠。因此，多嗜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。我们早期的研究有力地表明，宿主中生态型和多向性MuLV之间的相互作用在促进肿瘤发生中发挥了作用。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，方法是将多嗜性MuLV分离株和生态性MuLV株混合接种小鼠。与感染单一逆转录病毒的小鼠相比，感染特定逆转录病毒混合物的小鼠表现出显著的病理变化。这些包括一种多嗜性MuLV在引起增殖性疾病方面的非常显著的延迟，以及一种深刻的协同效应，导致与另一种多嗜性分离株突然发展成一种神经系统疾病。在这两种情况下，联合接种的小鼠的多嗜性病毒载量显着增加，而生态型MuLV的水平没有变化。此外，在联合接种的小鼠中，多嗜性MuLV几乎完全是生态型病毒粒子内的假型。有许多可能的机制可以促进多嗜性病毒在体内的深刻扩增，包括由于生态型病毒粒子内的伪分型而促进病毒的传播，或者可能是多嗜性病毒在共感染细胞中的反式激活。为了在一个不那么复杂的系统中检查这些问题，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，体外细胞株混合感染生态型和多性型MuLV后，其扩增和伪分型特征与我们在体内观察到的非常相似。在所有混合感染生态型MuLV和多性型MuLV的细胞系中，多性型MuLV基因组在生态型病毒粒子内广泛假型，在混合感染的细胞中感染性多角体病毒滴度显著升高。在混合感染和多嗜性MuLV的混合感染中，两性MuLV产生类似的结果。在该病例中，两性病毒粒子内的多嗜性MuLV是假型的，传染性多嗜性病毒滴度升高。这一结果表明，多嗜性MuLV在混合感染中的扩增并不局限于多嗜性病毒与其生态亲本的组合。从混合感染细胞释放的多嗜性MuLV感染力的提高可能是由于释放的多嗜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，生嗜性或两性嗜性病毒粒子的特定传染性要高得多。我们已经发现，在具有生性或两性MuLV的多嗜性MuLV混合物中，多嗜性病毒滴度的增加在很大程度上可以归因于从共感染细胞中包装和释放多嗜性基因组的效率的提高。

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.