Roles of Endogenous Retroviruses in Cancer and Auto-immune Diseases

包括人类和小鼠在内的哺乳动物的基因组中约有8%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件组成。我们基因组中的逆转录病毒插入数量约为40，000，与我们DNA编码的基因总数相同。大多数内源性逆转录病毒元件对于复制是有缺陷的，然而一些含有在发育和某些生理或病理条件期间表达的一个或多个病毒基因。关于逆转录病毒表达的控制或这种表达对宿主的生理或病理的影响知之甚少。一组广泛研究的内源性逆转录病毒是在小鼠中产生重组鼠白血病病毒（MuLV）的那些。 在用外源亲嗜性MuLV感染小鼠后，该组的成员经历重组以产生具有改变的感染宿主范围的新MuLV。 纯化需要内源性逆转录病毒的转录。 虽然内源性多变性前病毒被转录，但尚未观察到内源性多变性病毒在不存在重组的情况下复制。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因子活性的影响。外源性MuLV能够在小鼠中复制的事实表明，它们已经进化出了规避至少一些限制因子（如鼠APOBEC 3）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。我们已经发现，外源性病毒感染小鼠导致完整内源性前病毒基因序列的感染性转移。这包括严重缺陷并具有大缺失的前病毒以及全长前病毒。此外，转移的序列被转录并包装到从新感染的细胞释放的病毒体中。在Friend MuLV感染后的早期，完整内源性逆转录病毒的包装和转移比重组更为普遍。我们已经扩展了这些研究，发现内源性逆转录病毒的转移早在感染后一天就可以观察到，这表明包装发生在最初感染的细胞中的单个复制周期后。 此外，转移发生在衍生原型小鼠基因组序列的C57/B16小鼠。 这一发现将极大地促进包装的内源性转录本的表征。 C57/B16小鼠不产生重组多嗜性MuLV，因此我们的观察结果表明这种阻断不是由于内源性病毒的包装或转录。 完整的内源性逆转录病毒的动员是前所未有的，并可能有重要的影响，内源性逆转录病毒参与疾病过程。 内源性逆转录病毒包膜糖蛋白gp 70与小鼠狼疮性肾炎有关。该蛋白质由肝细胞分泌作为急性期蛋白，并且被认为是内源性异嗜性病毒的产物。然而，由于内源性多变性病毒编码与异嗜性gp 70密切相关的gp 70，因此这些病毒可能是血清gp 70的额外来源。为了更好地了解血清gp 70表达的遗传基础，我们分析了肝脏中异嗜性和嗜多性gp 70 RNA的丰度以及各种小鼠品系中相应内源性前病毒的基因组组成，包括两种不同的Sgp（血清gp 70产生）同源小鼠（Sgp 3和Sgp 4）。这些研究揭示了多变性gp 70对血清gp 70的显著贡献。 我们现在已经扩展了这些研究，以表明一个多变MuLV亚类的表达水平，称为修饰的多变（mPT），在发生系统性红斑狼疮的小鼠中高度升高。 这种升高的表达似乎对这类内源性病毒具有特异性，并且在Sgp 3基因座的控制下。 有趣的是，只有全长env转录本升高，而编码缺陷缺失env转录本的env基因没有升高。 .

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. Most endogenous retrovirus elements are defective for replication however 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 recombinant murine leukemia viruses (MuLVs) in mice. Upon infection of mice with exogenous ecotropic MuLVs, members of this group undergo recombination to generate new MuLVs with an altered infectious host range. Recombination requires transcription of the endogenous retroviruses. 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. We have extended these studies to find that that transfer of endogenous retroviruses can be observed as early as one day after infection indicating that packaging occurs after a single replication cycle in the initially infected cells. Further, transfer occurs from C57/Bl6 mice from which the prototypic mouse genomic sequence was derived. This finding will greatly facilitate the characterization of the packaged endogenous transcripts. C57/Bl6 mice do not generate recombinant polytropic MuLVs thus our observations indicate that this block is not due to packaging or transcription of the endogenous virus. 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 could 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 (Sgp3 and Sgp4). These studies revealed a significant contribution of polytropic gp70s to serum gp70. We have now exended these studies to show that expression levels of a subclass of polytropic MuLVs, termed, modified polytropic (mPT), are highly elevated in mice which develop systemic lupus erythematosus. This elevated expression appears specific for this class of endogenous viruses and under the control of the Sgp3 locus. Interestingly, only the full-length env transcripts are elevated while env genes encoding defective deleted env transcripts are not. .