Inhibition of reverse transcription in type I interferon mediated neuropathology

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.

Given that our cells are replete with DNA and RNA, the evolutionary adoption of viral nucleic acid recognition as the primary trigger of a type I interferon (T1I) mediated antiviral response carries with it the inherent risk of misconstruing self as non-self. Neurological disease is a major feature of the group of inborn errors of immunity referred to as the type I interferonopathies (T1IFNs), where enhanced T1I signalling is considered directly relevant to disease pathogenesis. An outstanding mechanistic question then relates to the source of self-derived nucleic acids that might drive such an inappropriate immune response in the non-infectious T1IFNs.

The conceptual distinction between self and non-self breaks down when considering endogenous retroelements. Indeed, given an important body of work implicating T1IFN-related genes in nucleic acid metabolism and retroelement biology, we have obtained promising preliminary data in a clinical trial of reverse transcriptase inhibitors (RTIs) in certain T1IFN genotypes, used on the premise that blocking the reverse transcription step in the lifecycle of LINE-1 (L1) elements, the only autonomous retroelement currently active in the human genome, might limit T1I induction. In the current project we wish to extend these data, proposing to challenge T1IFN patients with individual RTIs to determine if we can reduce autoinflammation by blocking reverse transcription, thereby implying a direct role for retroelements in human inflammatory disease.

In the absence of a neurological phenotype in equivalent animal models, possibly related to differences in the repertoire of active retroelements between species, experiments in the whole human organism are essential to progress our knowledge of T1IFN neuropathogenesis. Furthermore, given that T1I mediated neuropathology may be relevant in a number of other disease settings, these experiments will likely have broader significance for our understanding of neurological homeostasis.

Human interaction with viruses and other disease-causing organisms can be likened to an uneasy truce, punctuated by occasional skirmishes that can be fatal if an infectious agent develops the edge in the ongoing 'evolutionary arms race'. This stand-off between virus and humans demands constant vigilance, so that the development of mechanisms for recognising and responding to invasion by a pathogenic organism represents a major biological task. Evidence for such a conflict exists, in that up to 40% of human genetic material is derived from fragments of ancestral viral sequences (referred to as endogenous retroelements).

The type I interferon system is a central player in the ongoing battle against virus, given that type I interferons have a powerful antiviral effect and represent one of the first lines of defence against infection. Importantly, interferons are induced through the recognition of viral nucleic acids. Since the viral genome is a prerequisite for virus function, the detection of viral nucleic acids as a human, anti-viral immune strategy appears sensible. However, the existence of such viral nucleic acid sensors poses a biological difficulty; that is, how do such viral nucleic acid sensors avoid recognition of human (self) nucleic acid, given that our own cells are full of DNA and RNA? Indeed, the identification of a number of diseases associated with increased amounts of type I interferon, including the so-called human type I interferonopathies and other more common diseases, suggests that these mechanisms are imperfect and sometimes break down.

In this study we aim to investigate the possibility that certain diseases occur due to the induction of type I interferon signalling by endogenous retroelements (mentioned above). Depending on the results of our study, this work may provide major insight into a novel disease mechanism relating to the fundamental biological principle of self non-self discrimination. We will explore this question using a treatment strategy, involving the use of drugs called reverse transcriptase inhibitors. These drugs are extremely safe and well characterised, having been used in the treatment of millions of pregnant women, babies, children and adults worldwide (infected with the HIV-1 virus). If we see a treatment effect in the type I interferonopathies, this could have a very important impact for patients with the study diseases. That is to say, translation of our work into clinical practice might be possible in the short-term. Finally, there are other diseases also associated with enhanced type I interferon upregulation. Even if we are not yet sure if type I interferon represents a 'marker', as opposed to a 'driver', of these diseases, the risk-benefit ratio may indicate that clinical trials using the same drugs in other medical disorders are also warranted.