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的内源性包膜序列重组而成。外源性和内源性逆转录病毒基因组之间的重组需要将完整的内源性病毒转录成RNA链，该RNA链与外源性MuLV转录物共包装为异二聚体病毒粒子RNA。在随后的感染中，异源二聚体可以在逆转录过程中进行重组。虽然内源性多性原病毒被转录；没有观察到在没有重组的情况下内源性多性病毒的复制。在许多情况下，这可能反映了内源性病毒基因组中的缺陷，如点突变或缺失，但也可能受到各种限制性因子活性的影响。外源性mulv能够在小鼠体内复制的事实表明，它们已经进化出了规避至少一些限制性因子（如小鼠APOBEC3）活性的机制。因此，外源性逆转录病毒可能通过互补促进内源性逆转录病毒的主动复制。我们发现外源性病毒感染小鼠导致完整的内源性原病毒基因序列的感染性转移。这包括严重缺陷的原病毒和具有大缺失的原病毒以及全长的原病毒。此外，转移的序列被转录并包装成从新感染细胞释放的病毒粒子。在Friend MuLV感染后的早期，包装和转移完整的内源性逆转录病毒比重组更为普遍。完整内源性逆转录病毒的动员是前所未有的，可能对内源性逆转录病毒参与疾病过程具有重要意义。

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. Recombination between the exogenous and endogenous retrovirus genomes requires transcription of a complete endogenous provirus to an RNA strand which is co-packaged with an exogenous MuLV transcript as a heterodimeric virion RNA. Upon subsequent infection, the heterodimer can undergo recombination during reverse transcription. Although the endogenous polytropic proviruses are transcribed; replication of the endogenous polytropic viruses in the absence of recombination has not been observed. This may, in many cases, reflect defects such as point mutations or deletions in the endogenous viral genome but may also be influenced by the activity of various restriction factors. The fact that exogenous MuLVs are capable of replicating in mice indicates that they have evolved mechanisms to circumvent the activity of at least some of the restriction factors such as the murine APOBEC3. Thus, exogenous retroviruses might facilitate through complementation, active replication of endogenous retroviruses. We have found that infection of mice by an exogenous virus results in the infectious transfer of complete endogenous proviral genetic sequences. This includes proviruses which are severely defective and possess large deletions as well as proviruses that are full-length. Furthermore, the transferred sequences are transcribed and packaged into virions released from the newly infected cells. 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. The endogenous retroviral envelope glycoprotein, gp70 is implicated in murine lupus nephritis. This protein is secreted by hepatocytes as an acute phase protein and has been believed to be a product of an endogenous xenotropic virus. However, since endogenous polytropic viruses encode gp70s that are closely related to xenotropic gp70, these viruses can be additional sources of serum gp70. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of xenotropic and polytropic gp70 RNAs in livers and the genomic composition of corresponding endogenous proviruses in various strains of mice, including two different Sgp (serum gp70 production) congenic mice. These studies revealed a significant contribution of polytropic gp70s to serum gp70. Furthermore, injection of mice with lipopolysaccharides, a ligand for the toll-like receptor 4, selectively upregulated different classes of endogenous viruses indicating that that distinct retroviral gp70s are differentially regulated in physiological vs. inflammatory conditions.