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Open Access Publications from the University of California

Human immunodeficiency virus type-1 GU-rich ssRNA activates the NLRP3 inflammasome in macrophages through a non-canonical pathway

  • Author(s): To, Rachel
  • Advisor(s): Spector, Stephen A
  • et al.
No data is associated with this publication.

Human immunodeficiency virus type-1 (HIV) pathogenesis is associated with immune activation and chronic inflammation during active viral replication as well as during antiretroviral viral suppression. Even in cases where levels of replication competent virus are undetectable due to effective antiretroviral therapy, non-replicative virus is still produced with release of non-infectious viral RNA. This RNA is sensed by surveying innate immune cells, such as macrophages, which then induce pro-inflammatory cytokines such as interleukin-1 beta (IL-1β). Processing of IL-1β is associated with nod-like receptor protein-3 (NLRP3) inflammasome and caspase activation in many inflammatory diseases; however, the mechanism of IL-1β induction in human primary macrophages exposed to HIV RNA is unknown. To elucidate the mechanism of IL-1β activation by HIV RNA, we exposed human primary macrophages to RNA40 (a GU-rich ssRNA derived from the HIV long-terminal repeat region) and observed a significant induction of IL-1β. Processing of IL-1β in macrophages exposed to RNA40 required activation of the NLRP3 inflammasome independent of potassium efflux or reactive oxygen species production. RNA40 also triggered caspase-4 and -5 activation to mediate IL-1β release in a one-step event that occurs shortly after exposure to RNA40.

In total, these findings indicate that following exposure of human primary macrophages to GU-rich ssRNA from the HIV LTR region, the NLRP3 inflammasome is activated through a non-canonical pathway involving caspase-4 and caspase-5 to process IL-1β. This mechanism provides further insight into HIV pathogenesis, and suggests that targeting caspase-4 and caspase-5 could be useful in controlling HIV-associated chronic inflammation.

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This item is under embargo until April 4, 2021.