Abstract
Viral genomes comprise either RNA or DNA, and sometimes both, as can happen with retroviruses at different stages of their life cycle. Viral nucleic acids are pathogen-associated molecular patterns (PAMPs) that are detected by a variety of pathogen-recognition receptors (PPRs), key components of the innate immune system. A diverse set of PRRs has evolved to sense the genetic material of viruses. Toll-like receptors (TLRs) are archetypical PRRs, and several (TLR3, TLR7/8, and TLR9) recognize various RNA species and DNA CpG motifs in the endosomes. In addition, many cells also have RIG-I–like receptor (RLR) homologs that act as cytosolic sensors of viral RNA species (ssRNA or dsRNA with a 5′ppp group). The ligand specificities of these RLRs and the signaling cascades they induce are relatively well characterized (1). More recently, the discovery that intracellular DNA can induce an IFN response in a TLR-independent manner (2), and the identification of stimulator of IFN genes (STING) as a critical adaptor in the IFN-stimulatory DNA (ISD) pathway (3, 4), have stimulated the discovery of many cytosolic DNA sensors (5). However, our understanding of cytosolic DNA sensors in innate immune sensing is far from clear. Although numerous receptors have been proposed for the STING-dependent ISD pathway, a consistent definition of what constitutes a DNA-based STING-activating ligand is lacking. In PNAS, Jakobsen et al. provide evidence that the candidate DNA sensor IFI16 also serves a sensor of DNA forms generated during the lentiviral replication cycle and may serve to control or restrict HIV replication in myeloid human cell types (6).
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