An autoimmune disease prevented by anti-retroviral drugs

Beck-Engeser et al. Retrovirology 2011, 8:91http://www.retrovirology.com/content/8/1/91 An autoimmune disease prevented by anti-retroviral drugs Gabriele B Beck-Engeser1, Dan Eilat2 and Matthias Wabl1* Background: Both Aicardi-Goutières syndrome, a Mendelian mimic of congenital infection, and the autoimmunedisease systemic lupus erythematosus can result from mutations in the gene encoding the enzyme Trex1. In mice,the absence of Trex1 causes severe myocarditis. The enzyme is thought to degrade endogenous retroelements,thus linking them to autoimmune disease. However, inhibition of reverse transcription by the inhibitor zidovudine(AZT) did not ameliorate the disease, weakening the link to retroelements.
Findings: Here, we show that two other FDA-approved drugs that inhibit reverse transcriptase can ameliorate themyocarditis in Trex1-null mouse.
Conclusions: The result suggests that retroelements contribute to this hereditary form of autoimmunity, and thattreatment with retroelement inhibitors might ameliorate Aicardi-Goutières syndrome in humans.
Keywords: Aicardi-Gouti?è?res syndrome, myocarditis, Trex1, reverse transcriptase inhibitors disease with anti-retroviral agents. However, treatment Aicardi-Goutières syndrome (AGS) is a genetically- of the mice with the reverse transcription inhibitor azi- determined encephalopathy with remarkable phenotypic dothymidine (AZT) did not rescue the mice from lethal- overlap with the sequelae of congenital infection. Sys- ity [It was argued that the absence of Trex1 may temic lupus erythematosus (SLE) is an autoimmune dis- unleash hundreds of diverse reverse transcriptases ease characterized by the production of autoantibodies encoded by the mouse genome, some of them being that target nucleic acids and their associated proteins.
AZT resistant As a single agent, AZT also may Like AGS [SLE is associated with a perturbation of leave some retroelements out of its range of activity.
type I interferon metabolism []. Both AGS , and a Finally, although it leads to premature termination of cutaneous subtype of SLE called familial chilblain lupus cDNA synthesis, AZT has only little effect on the synth- can result from mutations in TREX1. Furthermore, esis of short reverse transcription intermediates, includ- mutations in TREX1 represent the single most common ing those of spliced retroelement products The cause of monogenic SLE identified to date interrupted or slowed reverse transcription may create Trex1 is a ubiquitous DNA 3' exonuclease that can persistent exposure to cytoplasmic DNA products that degrade retroelements (retroviruses and retrotranspo- elicit an antiviral innate immune response coordi- sons) In Trex1-deficient mice, single-stranded nated by activation of type I IFNs (the so-called IFN-sti- DNA derived from retroelement cDNA accumu- mulatory DNA response [Along this line, lates in the cytoplasm of cells in the heart and is raltegravir, a drug that inhibits retroviral integrase and thought to trigger the sterile inflammatory myocarditis thus increases the concentration of cDNA in the cell, On the basis that unrestricted retroelements may also exacerbates autoimmune disease cause, or at least contribute to, the disease it was In Trex1 deficient mice, the inflammation of the heart reasoned that it ought to be possible to treat or prevent muscle takes an aggressive course, with mice starting todie after 4 weeks of age (Figure ). We sought to pre- * Correspondence: vent the autoimmune disease with anti-retroviral drugs 1Department of Microbiology and Immunology, University of California, San other than AZT. Keeping in mind that a single drug Francisco, CA 94143-0414, USAFull list of author information is available at the end of the article may leave some retroelements out of its range of 2011 Beck-Engeser et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License ), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Beck-Engeser et al. Retrovirology 2011, 8:91 Figure 1 Effect of reverse transcriptase inhibitors on survival of Trex1-deficient mice. A) Inhibition of MLV cDNA synthesis by Truvada/Viramune. Flow cytometry graphs displaying GFP intensity generated by provirus: y-axis, cell number; x-axis, fluorescence intensity on alogarithmic scale. An MLV-based vector encoding GFP was added to NIH/3T3 cell cultures with 0, 100 nM, or 1 μM. B) Survival curves showingthe effect of Truvada/Viramune (+ drug; magenta circles) on Trex1-deficient mice obtained from D. Stetson The drugs were given fromconception via the drinking water as a solution of 3 × 10-4 M nevirapine, 1.6 × 10-4 M emtricitabine and 9.4 × 10-5 M tenofovir. Log rank test forthe drug effect, p = 0.000014. C) Hematoxylin-eosin stained sections of the left heart ventricle of treated (+ drug) and non-treated (- drug) micekilled at 9 and 7 months of age, respectively. Sections from three mice were examined in each category.
activity, we decided to use a combination of drugs that We first determined that the combination of Truvada inhibit reverse transcriptase. Because nucleoside reverse and Viramune is effective against MLV. Using flow cyto- transcription inhibitors also inhibit human LINE-1 retro- metry, we titrated the drug concentration for its ability transposition , we assumed that a Truvada/Viramune to inhibit expression of green fluorescence protein combination (both FDA-approved drugs) would inhibit encoded by MLV provirus upon infection; the EC50 was both classes of retroelements–retroviruses and retrotran- well below 100 nM (Figure When fed to Trex1- sposons. Truvada is a fixed-dose combination tablet con- deficient mice at a dose comparable to that given to taining emtricitabine and tenofovir disoproxil fumarate patients with HIV, the drugs substantially reduced mor- Emtricitabine is a synthetic nucleoside analog of tality (Figure On sections of the heart from 9- cytidine. Tenofovir disoproxil fumarate is converted in month old treated mice, there were some mild patchy vivo to tenofovir, an acyclic nucleoside phosphonate inflammatory infiltrates with little myocyte injury; but (nucleotide) analog of adenosine 5'-monophosphate. Vir- the difference to the marked inflammatory infiltrates amune (nevirapine) blocks the reproduction of retro- with myocyte necrosis and dropout in 7-month old virus earlier in its cycle than Truvada. It binds directly to non-treated mice (at 9 months all untreated mice were reverse transcriptase and blocks the RNA-dependent and dead) was striking (Figure DNA-dependent DNA polymerase activities by disrupt- Almost half of the human genome consists of retroele- ing the enzyme's catalytic site. Viramune does not com- ments, many of them active. There are several ways that pete with template or nucleoside triphosphates, or inhibit retroelements might trigger an autoimmune response, the cellular DNA polymerases tested so far including (i) sensing of retroelement RNA and cDNA, Beck-Engeser et al. Retrovirology 2011, 8:91 (ii) generation of mimetopes through error-prone Lindahl T, Barnes DE, Yang YG, Robins reverse transcription of mRNA encoding retroelement Biochem Soc Trans 2009, 37:535-538.
proteins, and (iii) insertional mutagenesis. We showed Stetson DB, Ko JS, Heidmann T, Medzhitov here that a hereditary autoimmune inflammation in the Cell 2008, 134:587-598.
mouse that is likely caused by accumulation of retroele- Beck-Engeser GB, Eilat D, Harrer T, Jack HM, Wabl Proc ment cDNA can be treated with reverse transcriptase Natl Acad Sci USA 2009, 106:20865-20870.
inhibitors. Other autoimmune diseases might be amen- Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J: able to different interventions of retroelement activities.
Nat Immunol 2010,11:1005-1013.
Yang YG, Lindahl T, Barnes AZT: zidovudine; AGS: Aicardi-Goutières syndrome; IFN: interferon; MLV: 2007, 131:873-886.
murine leukemia virus; SLE: systemic lupus erythematosus.
Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G,Lindahl T, Barnes DE: We thank Dan Stetson for the Trex1-deficient mice; Jean Olson for the 2004, 24:6719-6727.
micrographs; Cliff Wang and Jay Lalezari for suggestions; and Mary Quan Y, Liang C, Inouye P, Wainberg MA: McKenney for editing the manuscript. Supported by grants from the NIH (R01AI041570) and the Lupus Research Institute to MW; and from the United Nucleic Acids Res 1998, States - Israel Binational Foundation (BSF) to MW and DE.
Houzet L, Morichaud Z, Mougel M: 1Department of Microbiology and Immunology, University of California, San Retrovirology 2007, 4:30.
Francisco, CA 94143-0414, USA. 2Department of Medicine, Hadassah Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, University Hospital and The Hebrew University Faculty of Medicine, Hebbeler AM, Greene Jerusalem 91120, Israel.
Authors' contributions Stetson DB, Medzhitov R: GBE, DE, and MW planned the study; GBE carried out the experiments; and Immunity 2006, 24:93-103.
MW wrote the manuscript. All authors read and approved the final Jones RB, Garrison KE, Wong JC, Duan EH, Nixon DF, Ostrowski MA: PLoS ONE 2008, 3:e1547.
Competing interests The authors declare that they have no competing interests.
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