Roles of Cyclic GMP-AMP Synthase in Immune Defense Against Retroviruses and Autoimmunity

The presence of DNA in the cytosol is known to trigger robust innate immunity. Cyclic GMP-AMP synthase (cGAS) is the sensor of cytosolic DNA and activation of cGAS initiates cytokine production. Here we show cGAS plays essential roles in immune defense against retroviruses as well as in autoimmune diseases caused by self-DNA. HIV infection abrogates adaptive immunity by the depletion of CD4 T cells. However, innate immune defense mechanisms against HIV are largely unknown. We show that pseudotyped HIV can infect human and mouse cell lines, leading to the production of interferons (IFN) and other antiviral cytokines. Activation of innate immunity by HIV requires viral cDNA synthesis but not cDNA integration. Furthermore, retrotranscribed HIV cDNA is sensed by the cytosolic DNA sensor cGAS, which then produces the second messenger 2'3'-cyclic GMP-AMP (cGAMP) to activate the adaptor STING. Importantly, wild-type HIV also triggers cGAMP production in human primary macrophages, underscoring the key role of cGAS in HIV sensing. Moreover, cytosolic sensing of other retroviruses such as murine leukemia virus and simian immunodeficiency virus also depends on cGAS. cGAS is important for the immune response against retroviruses, however, overactive cGAS causes autoimmunity. TREX1 is a cytosolic DNase which clears mislocalized DNA in the cytosol. Loss-of-function mutations in TREX1 cause the human disease Aicardi-Goutières syndrome (AGS). AGS manifests with abnormal type I IFN production and inflammation in multiple organs. Trex1-/- mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of IFN-induced genes (ISGs). Here we show that genetic ablation of cGAS in Trex1-/- mice eliminates all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Similarly, deletion of cGAS in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescues the lethal autoimmune phenotype of the DNaseII-/- mice. Also, polyarthritis in DNaseII-/- Ifnar1-/- mice is dependent on cGAS. These results improve our understanding of immune detection of HIV and provide cGAMP as a new adjuvant for developing HIV vaccines. Moreover, our results suggest that inhibition of cGAS may lead to new treatments of some human autoimmune diseases caused by self-DNA.