Abortive HIV‐1 RNA induces pro‐IL‐1β maturation via protein kinase PKR and inflammasome activation in humans

The proinflammatory cytokine IL‐1β mediates high levels of immune activation observed during acute and chronic human immunodeficiency virus 1 (HIV‐1) infection. Little is known about the mechanisms that drive IL‐1β activation during HIV‐1 infection. Here, we have identified a crucial role for abortive HIV‐1 RNAs in inducing IL‐1β in humans. Abortive HIV‐1 RNAs were sensed by protein kinase RNA‐activated (PKR), which triggered activation of the canonical NLRP3 inflammasome and caspase‐1, leading to pro‐IL‐1β processing and secretion. PKR activated the inflammasome via ROS generation and MAP kinases ERK1/2, JNK, and p38. Inhibition of PKR during HIV‐1 infection blocked IL‐1β production. As abortive HIV‐1 RNAs are produced during productive infection and latency, our data strongly suggest that targeting PKR signaling might attenuate immune activation during acute and chronic HIV‐1 infection.