Inhibition of reverse transcription in type I interferon mediated neuropathology

aicardii - gouti<e:1>综合征（AGS）是一种严重的儿童期脑部疾病，与一种名为I型干扰素的化学物质水平非常高有关。正常情况下，我们只有在被病毒感染时才会产生干扰素。AGS组无明显病毒感染。相反，由于这些个体的遗传密码（包含在我们的“DNA”中）发生了变化（突变），我们认为体内的细胞被愚弄，认为这个人自己的DNA是病毒——也就是说，在区分“自我”和“非自我”时存在混淆。事实上，我们自身的大量DNA是由古老的病毒（“内源性逆转录病毒”）组成的，它们在数百万年的时间里被我们带入了我们的遗传物质中——有时被称为“垃圾”DNA。这些内源性逆转录病毒仍然可以像来自体外的病毒一样发挥作用，所以它们需要被控制。我们想知道导致AGS的基因变化是否意味着这些正常的控制机制不起作用。如果这是真的，内源性逆转录病毒将开始自我复制，这可能会被我们的免疫系统识别为“外来”，导致干扰素的持续产生，然后破坏我们体内的细胞。由于我们无法修复每个细胞中的遗传密码，我们希望用一种叫做逆转录酶抑制剂（RTIs）的药物治疗AGS患者。rti被用来对抗导致艾滋病的HIV-1病毒。在AGS的情况下，我们没有治疗HIV-1，但我们想知道同样的药物是否能够控制内源性逆转录病毒，我们认为是驱动干扰素产生。事实上，在最近完成的一项研究中，使用这种治疗方法，我们收集到的早期信息表明，在一年内，我们确实看到了患者体内干扰素水平的下降，当我们停止用药时，干扰素水平上升。此外，从科学的角度来看，这些研究对AGS患者及其家属具有重要的潜在意义。从科学上讲，如果结果支持垃圾DNA有时与人类疾病有关的可能性，我们的项目将会引起相当大的兴趣。rti是一种非常安全的药物，已经在世界各地数以百万计的HIV-1患者中使用。如果我们的研究结果令人信服，我们相信可能也值得考虑治疗其他疾病，这些疾病也被证明与I型干扰素水平升高有关，包括更常见的免疫疾病，即系统性红斑狼疮。

Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally, we only produce interferon when we are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code (contained in our 'DNA') in these individuals, we believe that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'. In fact, a large amount of our own DNA is made up of ancient virus ('endogenous retrovirus'), that we have taken into our genetic material over millions of years - sometimes referred to as 'junk' DNA. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. We have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that was true, the endogenous retroviruses would start to make copies of themselves which could be recognised by our immune system as 'foreign', leading to the continuous production of interferon which then damages the cells in our body. Since we cannot repair the genetic code in every cell, we wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, we are not treating HIV-1, but we wonder if the same drugs might be able to control endogenous retroviruses that we think are driving interferon production. Indeed, using this treatment in a recently completed study we gathered early information to suggest that we did see a reduction in interferon levels in patients over a one year period, with levels of interferon increasing when we stopped the drugs. Additionally, from a scientific point of view, these studies are of great potential importance for patients with AGS and their families. Scientifically, our project will be of considerable interest if the results support the possibility that junk DNA can sometimes be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If our results turn out to be convincing, we believe that it might also be worth thinking about treating other diseases that have also been shown to be associated with increased levels of type I interferon, including the much more common immune condition called systemic lupus erythematosus.