Retroviruses are adept at evading recognition by the host immune system. However, recent studies have shown that these viruses can induce innate immune responses. The cellular sensor that recognizes retroviruses has nevertheless been unclear. Daxing Gao et al. now report that the cyclic GMP-AMP synthase (cGAS) that they previously found senses DNA viruses, such as vaccinia virus, is also capable of triggering an interferon (IFN) response to retroviral DNA (Science, http://dx.doi.org/10.1126/science.1241800).

The authors found that infection of a monocytic cell line with a modified HIV-1 virus induced IFN-β production, which was blocked by inhibiting reverse transcription of the retroviral genome. Cytosolic DNA can bind and activate cGAS, resulting in the formation of cGAMP from ATP and GTP. cGAMP, in turn, activates stimulator of interferon genes (STING), eventually leading to the induction of cytokines and interferons. The authors showed that cGAS and STING were also required for sensing retroviral cDNA and that the retroviral cDNA was required for induction of cGAMP production by cGAS, which triggered the subsequent IFN response pathway. The authors extended their findings to primary human monocyte-derived macrophages and monocyte-derived dendritic cells that were rendered permissible to HIV-1 infection, and they further showed that the same pathway was active in sensing SIV and murine leukemia virus. These findings lend support to the idea that retroviruses are not invisible to the immune system, and they suggest a pathway for possible intervention to enhance their immune recognition.