Abstract
Human macrophages at mucosal sites are essential targets for acute HIV infection. During the chronic phase of infection, they are persistent reservoirs for the AIDS virus. HIV virions gain entry into macrophages following ligation of surface CD4-CCR5 co-receptors, which leads to the release of two copies of HIV ssRNA. These events lead to reverse transcription and viral replication initiation. Toll-like receptors TLR7 and TLR8 recognize specific intracellular viral ssRNA sequences, but in human alveolar macrophages, their individual roles in TLR-mediated HIV ssRNA recognition are unclear. In the current study, HIV-1 ssRNA induced TNFα release in a dose-dependent manner in adherent human macrophages expressing both intracellular TLR7 and TLR8. This response was reduced by inhibiting either endocytosis (50 μm dynasore) or endosomal acidification (1 μg/ml chloroquine). Either MYD88 or TLR8 gene knockdown with relevant siRNA reduced HIV-1 ssRNA-mediated TNFα release, but silencing TLR7 had no effect on this response. Furthermore, HIV-1 ssRNA induced histone 4 acetylation at the TNFα promoter as well as trimethylation of histone 3 at lysine 4, whereas TLR8 gene knockdown reduced these effects. Taken together in human macrophages, TLR8 binds and internalizes HIV ssRNA, leading to endosomal acidification, chromatin remodeling, and increases in TNFα release. Drugs targeting macrophage TLR8-linked signaling pathways may modulate the innate immune response to acute HIV infection by reducing viral replication.
Highlights
TLR7/TLR8 recognize viral ssRNA, but in human macrophages recognition of HIV-1 ssRNA is not known
Dose-dependent Effects of HIV-1 ssRNA on TNF␣ Release in Human Macrophages—HIV-1 induces increase in TNF␣ release in primary dendritic cells (pDCs) via TLR7 [6]
We demonstrated that in human macrophages, increases in pro-inflammatory cytokine TNF␣ release occur through selective recognition by endosomal TLR8 of uridinerich HIV-1 ssRNA oligonucleotides
Summary
TLR7/TLR8 recognize viral ssRNA, but in human macrophages recognition of HIV-1 ssRNA is not known. HIV-1 ssRNA induced TNF␣ release in a dose-dependent manner in adherent human macrophages expressing both intracellular TLR7 and TLR8 This response was reduced by inhibiting either endocytosis (50 M dynasore) or endosomal acidification (1 g/ml chloroquine). We show that HIV-1 ssRNA mediates TLR8 linked pathway signaling activation through post-translational histone modification followed by increase in transcription factor binding to TNF␣ promoters. These results suggest that drug targeting macrophage TLR8 signaling pathways and enzymes/proteins involved in inducing epigenetic changes may provide a novel approach to deciphering HIV pathogenesis and to correct dysregulated innate immune responses to HIV infection
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