HCV and HIV stimulate production of the inflammatory cytokine IL-18 through activation of the Nalp3 inflammasome in monocytes (108.12)

Abstract

Abstract Activation of the inflammasome-complex leads to production of the pro-inflammatory, inflammasome-associated cytokines IL-18 and IL-1β. These cytokines amplify the innate antiviral immune response and skew the developing adaptive immune response. We previously reported that IL-18 is the earliest host response to hepatitis C virus (HCV) infection and remains elevated at low levels in chronic infection. Our group has also reported an association between IL-18 SNPs and likelihood of HCV clearance. Despite these observations, the role of IL-18 in control of viruses capable of chronic infection is unknown. We now show that IL-18 is also elevated in persons with uncontrolled HIV and to a lesser extent in those with natural immunologic control of the virus. To understand inflammasome activity during chronic viral infection, we studied the interaction of HCV or HIV infected plasma and PBMC subsets from HIV and HCV uninfected subjects. We determined that (1) monocytes cultured with plasma from HIV or HCV viremic individuals produce IL-18 and other pro-inflammatory cytokines; (2) the virion is the inflammasome stimulating component within plasma, (3) siRNA knockdown of Nalp3 in monocytes modulates HCV and HIV induction of IL-18. Our data elucidate mechanisms by which HCV and HIV activate the inflammasome complex and demonstrate the production of inflammatory cytokines through the interaction of HIV and HCV and monocytes.