HIV-1 Infection Induces IL-1{beta} Production via TLR8-Dependent and NLRP3-Inflammasome Mechanisms in Human Monocytes [Microbiology]

June 17th, 2014 by Guo, H., Gao, J., Taxman, D. J., Ting, J. P. Y., Su, L.

Induction of inflammatory cytokines such as IL-1β is associated with the progression of HIV-1 disease or acquired immune deficiency syndrome (AIDS). Unlike most inflammatory cytokines that are regulated by NF-κB at the transcriptional level, production of mature IL-1β also depends on inflammasome activation. The mechanism by which HIV-1 induces pro-IL-1β expression and activates inflammasomes to cleave pro-IL-1β into its bioactive form is not clear defined. We report here that HIV-1 infection in human monocytes efficiently induced IL-1β expression and inflammasome activation. Toll like receptor 8 (TLR8) was required for inducing pro-IL-1β expression, whereas the NLRP3 inflammasome was required for the IL-1β maturation and release. Furthermore, lysosomal protease cathepsin B and HIV-1 induced production of reactive oxygen species (ROS) were critical for HIV-induced inflammasome activation and IL-1β production. HIV-1 entry, reverse transcription and integration were all required for both pro-IL-1β expression and inflammasome activation. Finally, we show that HIV-1 derived RNA was sufficient to induce both pro-IL-1β expression and inflammasome activation. We conclude that HIV-1 infection induced expression of pro-IL-1β via TLR8-mediated mechanisms and activated caspase-1 through NLRP3 inflammasome to cleave pro-IL-1β into bioactive IL-1β. These findings help to elucidate mechanisms of HIV-1 disease progression and identify novel targets for treating HIV-1 induced inflammation and immune activation.