Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs.

Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus-like disease Aicardi-Goutières syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP-AMP synthase-dependent type I IFN response and systemic autoimmunity. Products of reverse transcription originating from endogenous retroelements have been suggested to be a major substrate for TREX1, and reverse transcriptase inhibitors (RTIs) were proposed as a therapeutic option in autoimmunity ensuing from defects of TREX1. In this study, we treated mice with RTIs. The serum RTI levels reached were sufficient to block retrotransposition of endogenous retroelements. However, the treatment did not reduce the spontaneous type I IFN response and did not ameliorate lethal inflammation. Furthermore, long interspersed nuclear elements 1 retrotransposition was not enhanced in the absence of Trex1. Our data do not support the concept of retroelement-derived cDNA as key triggers of systemic autoimmunity in Trex1-deficient humans and mice and motivate the continuing search for the pathogenic IFN-inducing Trex1 substrate.