LAUSR

Cytosolic recognition of microbial DNA in macrophages results in the activation of the interferon (IFN)‐dependent antiviral innate immunity. Here, we examined whether activating DNA sensors in peripheral blood monocyte‐derived macrophages (MDMs) can inhibit human immunodeficiency virus (HIV). We observed that the stimulation of MDMs with poly(dA:dT) or poly(dG:dC) (synthetic ligands for the DNA sensors) inhibited HIV infection and replication. MDMs treated with poly(dA:dT) or poly(dG:dC) expressed higher levels of both type I and type III IFNs than untreated cells. Activation of the DNA sensors in MDMs also induced the expression of the multiple intracellular anti‐HIV factors, including IFN‐stimulated genes (ISGs: ISG15, ISG56, Viperin, OAS2, GBP5, MxB, and Tetherin) and the HIV restriction microRNAs (miR‐29c, miR‐138, miR‐146a, miR‐155, miR‐198, and miR‐223). In addition, the DNA sensor activation of MDM upregulated the expression of the CC chemokines (RANTES, MIP‐1α, MIP‐1β), the ligands for HIV entry coreceptor CCR5. These observations indicate that the cytosolic DNA sensors have a protective role in the macrophage intracellular immunity against HIV and that targeting the DNA sensors has therapeutic potential for immune activation‐based anti‐HIV treatment.