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

Kathy Triantafilou,Seth L Masters,Louise K Modis,Curt Haffner,Martha Triantafilou,Christopher J K Ward,Robert G Ferris,Vipulkumar K Patel,Emma Koppe,Magdalena Czubala,Heather Amrine-Madsen,Vincent Piguet,Charles R M Bangham

doi:10.1371/journal.ppat.1009417

Abstract

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-1β 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-1β/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.

Highlights

CD4+ T-cells might be the primary target of Human immunodeficiency virus (HIV), cells of the myeloid lineage, such as monocytes, macrophages and mDCs are relevant cell types capable of being the target as well as the reservoir for HIV-1 infection
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 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

Summary

Introduction

CD4+ T-cells might be the primary target of Human immunodeficiency virus (HIV), cells of the myeloid lineage, such as monocytes, macrophages and mDCs are relevant cell types capable of being the target as well as the reservoir for HIV-1 infection. The significance of the infection of macrophages by HIV is well established in the fact that as the infection progresses, CD4+ T-cells are depleted and individuals become increasingly macrophage-tropic [1]; with macrophages becoming the main long-lived HIV reservoir [2,3] To their role in infection, an additional role for monocytes/ macrophages and mDCs is emerging, where they contribute to a chronic immune activation leading to pathogenic mechanisms associated with HIV. This dysregulated chronic immune activation is the key factor in co-morbidities associated with HIV [4], such as cardiovascular disease [5,6,7], HIV-associated neurological disorders [8], HIV-associated dementia (HAD) [9], immune aging [10,11] as well as all-cause mortality [12,13]. This chronic inflammation is observed in individuals who are not receiving anti-retroviral therapy (ART), and in individuals who show no detectable levels of HIV RNA in the absence of ART [14]

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Conclusion