Influence of Mixed Retrovirus Infections on Leukemia and Neurological disease

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。

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 an in vitro cell line. In 2012 we have continued studies of mixed retrovirus infections of in vitro cell lines. We have confirmed that co-infection of polytropic MuLVs with ecotropic or amphotropic viruses results in amplification and pseudotyping characteristics remarkably similar to what we have observed in vivo. The polytropic infectivity released from co-infected cells is markedly increased while the ecotropic infectivity remains unaltered. Further, the increase in infectivity is accompanied by extensive pseudotyping of the polytropic genome within ecotropic virions. This observation extended to cell lines from different tissues and different mice indicating that it was a feature of the components of the mixed infection rather than a property of the cells. 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, possibly reflecting an inherent defectiveness of the polytropic envelope. In this regard, unlike ecotropic and amphotropic viruses, recombinant polytropic viruses are chimeric viruses in which the envelope of the virus has not co-evolved with the other structural genes. Thus the envelope protein of polytropic viruses may not function as efficiently in packaging and release of progeny viruses.