Differential recognition of HIV-stimulated IL-1β and IL-18 secretion through NLR and NAIP signalling in monocyte-derived macrophages

Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus the later phases infection is often predominantly macrophage-tropic this tropism contributes a chronic inflammatory immune activation state that observed patients. Pattern recognition receptors innate system key molecules recognise mount responses macrophages. response against HIV-1 potent elicits caspase-1-dependent pro-inflammatory cytokine production IL-1β IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating little known about pattern trigger “priming” signal for activation, NLRs involved or components response. Using combination siRNA knockdowns monocyte derived macrophages (MDMs) different TLRs well chemical inhibition, it was demonstrated Vpu could via TLR4/NLRP3 leading IL-1β/IL-18 secretion. priming triggered TLR4, whereas by direct effects on Kv1.3 channels, causing K + efflux. In contrast, gp41 IL-18 NAIP/NLRC4, independently priming, one-step activation. NAIP binds directly cytoplasmic tail envelope protein represents first non-bacterial ligand NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets resolve specific pathologies associated with