Genetic Structure Of Murine Retroviruses

哺乳动物（包括人类和小鼠）大约8%的基因组是由在进化过程中通过生殖系细胞感染获得的逆转录病毒元素组成的。我们基因组中逆转录病毒的插入数约为4万个，与我们DNA编码的基因总数相同。许多内源性逆转录病毒元件是有缺陷的，但有些似乎是完整的，有些含有在发育和某些生理或病理条件下表达的一个或多个病毒基因。关于逆转录病毒表达的控制以及逆转录病毒表达对宿主生理病理的影响，我们所知甚少。广泛研究的一组内源性逆转录病毒是那些在小鼠中引起多嗜性小鼠白血病病毒（mulv）的病毒。在一些情况下，多性mulv直接涉及发病机制，包括诱导增殖性、免疫和神经系统疾病。多嗜性mulv是由外源性生态性mulv与近交系小鼠基因组中存在的内源性包膜序列重组而形成的，它们的产生导致混合逆转录病毒感染。我们研究了逆转录病毒在小鼠体内混合感染中的相互作用，通过共接种多性和生态性mulv，观察到不同病毒混合物诱导的疾病类型和速度的显着变化。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。在第一种情况下，疾病诱导的延迟与体内逆转录病毒干扰相关，导致在感染外源性生态性MuLV后通常观察到的新的多性MuLV的产生受到抑制。神经系统疾病的快速发展伴随着生态病毒粒子内多性MuLV基因组的广泛假分型，以及共接种小鼠中多性MuLV感染和复制的显著升高。

Approximately 8% of the genomes of mammals, including humans and mice, are comprised of retroviral elements acquired by infection of germ line cells during the course of evolution. Retroviral insertions in our genome number about 40,000 and are in the same range as the total number of genes encoded by our DNA. Many endogenous retrovirus elements are defective, however some appear to be intact, and several contain one or more viral genes that are expressed during development and certain physiological or pathological conditions. Little is known about the control of retrovirus expression or the influence of such expression on the physiology or pathology of the host. An extensively investigated group of endogenous retroviruses are those giving rise to polytropic murine leukemia viruses (MuLVs) in mice. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including 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 and their generation results in a mixed retrovirus infection. We have investigated the interactions of retroviruses in mixed infections in vivo by co-inoculation of mice with polytropic and ecotropic MuLVs and observed remarkable alterations in the types and tempo of disease induced by different mixtures of viruses. 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 the first case the delay in disease induction correlated with in vivo retroviral interference resulting in the suppression the generation of new polytropic MuLVs normally observed after infection with the exogenous ecotropic MuLV. The rapid development of neurological disease were accompanied by extensive pseudotyping of the polytropic MuLV genome within ecotropic virions and a striking elevation of polytropic MuLV infection and replication in co-inoculated mice. Another aspect of our studies involves the characterization of the family of endogenous retroviruses that participate in recombination to yield polytropic MuLVs. Structural studies of these endogenous viruses suggest that they have undergone recent periods of active replication. We have found that mice infected with exogenous retroviruses release infectious virus particles containing RNA sequences corresponding to complete transcripts of the endogenous proviruses. At early times after infection with the Friend MuLV, packaging and transfer of intact endogenous retroviruses is much more prevalent than recombination. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes.