Publications

Triantafilou, K; Ward, CJK; Czubala, M; Ferris, RG; Koppe, E; Haffner, C; Piguet, V; Patel, VK; Amrine-Madsen, H; Modis, L; Masters, SL; Triantafilou, M (2021). Differential recognition of HIV-stimulated IL-1 beta and IL-18 secretion through NLR and NAIP signalling in monocyte-derived macrophages. PLOS PATHOGENS, 17(4), e1009417.

Abstract
Author summary It has been previously shown that inflammasome activation can be triggered during viral infection to produce the active cytokines IL-1 beta and IL-18. Our study represents a significant advance, as we now show that in fact there are distinct NLR inflammasome complexes and viral ligands for IL-1 beta secretion (Vpu) compared to IL-18 secretion (gp41) in response to HIV-1. Most importantly, we show that the HIV envelope protein gp41 represents the first non-bacterial ligand for the assembly of the NAIP/NLRC4 inflammasome. HIV gp41 is a viroporin, and thus our data demonstrates for the first time that the NAIP/NLRC4 inflammasome assembles for all pore-forming proteins, irrespective of whether they have a viral or bacterial origin. This is critical for the host antiviral response and has broad implications for innate immunity in general. Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1 beta and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the "priming" signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1 beta/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages.

DOI:
10.1371/journal.ppat.1009417

ISSN:
1553-7366