Human immunodeficiency virus Type‐1 single‐stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia

Abstract

Despite the availability of antiretroviral therapy (ART) that fully suppresses human immunodeficiency virus type-1 (HIV), markers of inflammation and minor neurocognitive impairment are frequently identified in HIV-infected persons. Increasing data support that low level replication defective viral RNA is made by infected cells despite the absence of infectious virus. Specific GU-rich single-stranded RNA from the HIV long terminal repeat region (ssRNA40) signaling through toll-like receptor (TLR)-7 and -8 has been shown to induce the secretion of interleukin-1β (IL-1β) in primary monocytes. Here, we examined the activation of microglial cells by HIV ssRNA40, and the potential subsequent neurotoxicity. Our findings show that exposure of human primary microglia to ssRNA40 activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Following exposure to ssRNA40, pro-inflammatory cytokines IL-1β, IL-18 and neurotoxic cytokines TNF-α, IL-1α and C1q expression and extracellular secretion are increased. The released cytokines are functional since culture supernatants from ssRNA40 exposed microglia induced toxicity of human primary neurons. Moreover, inflammasome activation of microglia increased ROS generation with a loss of mitochondrial membrane potential and mitochondrial integrity. Treatment with ssRNA40 resulted in a blockade of autophagy/mitophagy mediated negative regulation of NLRP3 inflammasome activity with release of inflammatory cytokines, caspase-1 activation and pyroptotic microglial cell death. Thus, HIV ssRNA mediated activation of microglial cells can contribute to neurotoxicity and neurodegeneration via secretion of inflammatory and neurotoxic cytokines. These findings provide a potential mechanism that explains the frequent minor cognitive deficits and chronic inflammation that persist in HIV-infected persons despite treatment with suppressive ART.

NLRP3 Inflammasome—A Key Player in Antiviral Responses

“…Mitochondria damage is also a crucial activator of the NLRP3 inflammasome. Similar to lysosomal or endosomal maturation, mitochondria damage also induces the production of ROS to activate the NLRP3 inflammasome (56,57). The RIP1-RIP3 complex, assembled after viral infection, induces activation of the GTPase DRP1.…”

Regulation of Innate Immune Responses by Autophagy: A Goldmine for Viruses

“…Indeed, IAV recognition by the NOD receptor induces mitophagy, therefore restraining inflammasome activation ( 116 ). During HIV-1 infection, abortive infection of astrocytes or infection of microglial cells triggers inflammasome activation ( 142 ). However, in productive infection of astrocytes, mitophagy is induced and regulates this process ( 117 ).…”

Interplays between inflammasomes and viruses, bacteria (pathogenic and probiotic), yeasts and parasites

“…For example, in in vitro experiments on human primary neurons (HPNs) and microglial cells (HFMG) collected from healthy patients, it was discovered that treatment of the cells with HIV ssRNA40 (specific GU-rich single-stranded RNA from the HIV long terminal repeat region) activates the NLRP3 inflammasome and increases the expression and extracellular secretion of pro-inflammatory cytokines (IL-1β, IL-18) and neurotoxic cytokines (TNF-α, IL-1α, C1q). HIV ssRNA40 causes a blockade of autophagy/mitophagy-mediated negative regulation of NLRP3 inflammasome activity with the release of inflammatory cytokines, caspase-1 activation, and pyroptotic microglial cell death [ 22 ]. Another report has shown that HIV-1 induces the expression of NLRP3 inflammasome and IL-1β secretion in dendritic cells from healthy individuals but not HIV-1-infected patients, suggesting that inflammasome activation contributes to disease progression [ 23 ].…”

“… [ 17 ] HIV ssRNA40 Activates the NLRP3 inflammasome and increases the expression and extracellular secretion of pro-inflammatory cytokines (IL-1β, IL-18) and neurotoxic cytokines (TNF-α, IL-1α, C1q). [ 22 ] SARS-CoV E, ORF3a and ORF8b viroporin proteins SARS-CoV E induces Ca2+ leakage to the cytosol from Golgi storage and ORF3a protein induce K + efflux at the plasma membrane to the extracellular spaces. The imbalance in the ionic concentration in the cells, generated by damaged mitochondria ROS lead to NLRP3 inflammasome activation.…”