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。为了在不那么复杂的环境中研究这种现象，我们目前正在利用体外细胞系检测混合逆转录病毒感染。我们发现，混合感染具有生态型和多向性MuLV的体外细胞株，其扩增和伪分型特征与我们在体内观察到的非常相似。值得注意的是，在生态型病毒粒子中，多嗜性MuLV基因组被广泛地假型，而在混合感染的细胞中，传染性多嗜性病毒的滴度显著升高。这一观察结果可能是由于细胞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与多嗜性病毒相比，生态型病毒粒子的特定传染性要高得多。进一步的研究有力地表明，多角体病毒滴度的增加不是由于特定感染性的差异，而是由于多角体基因组在合并感染细胞中包装和释放效率的提高。。

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. 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. .