HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

Abstract

Microglia play a central role in the pathogenesis of HIV-associated dementia not only by acting as conduits of viral entry but also as reservoirs for productive and latent virus infection, and as producers of neurotoxins. Interaction between CX3CL1 (fractalkine) and FKN receptor (CX3CR1) is highly functional in the brain, and is known to regulate a complex network of paracrine and autocrine interactions between neurons and microglia. The purpose of the present study was to determine what extent HIV-1 Tat protein causes the alteration of CX3CR1 expression and to investigate the regulatory mechanism for CX3CR1 expression. Here we showed that exposure of primary microglia and BV2 cells to exogenous Tat protein resulted in down-regulation of CX3CR1 expression at both the mRNA and protein levels, with a concomitant induction of proinflammatory responses. Next, we further showed that NF-κB activation by Tat treatment negatively regulated CX3CR1 expression. Since a YY1 binding site ~10kb upstream of CX3CR1 promoter was predicted in rats, mice and humans, the classical NF-κB-YY1 regulatory pathway was considered. Our findings indicated that Tat repressed CX3CR1 expression via NF-κB-YY1 regulatory pathway. To gain insight into the effect of Tat on CX3CL1-CX3CR1 communication, calcium mobilization, MAPK activation and microglial migration, respectively, were tested in microglial cells after successive treatment with Tat and CX3CL1. The results suggested that Tat disrupted the responses of microglia to CX3CL1. Taken together, these results demonstrate that HIV-1 Tat protein suppresses CX3CR1 expression in microglia via NF-κB-YY1 pathway and attenuates CX3CL1-induced functional response of microglia.

Mesenchymal Stem Cells Modulate the Functional Properties of Microglia via TGF-β Secretion

“…CX3CL1 is known to modulate a complex network of paracrine and autocrine interactions between neurons and microglia, controlling microglia neurotoxicity [11]. A recent study showed that activation of the NF-kB pathway inhibited CX3CR1 expression in microglia via yy1 and led to attenuated functional responses of microglia to CX3CL1 [36]. Our results also showed that MSC-CM inhibited the NF-kB pathway, restored Smad2/3 phosphorylation, and normalized CX3CR1 expression in LPS-stimulated microglia.…”

Immune activation in the central nervous system throughout the course of HIV infection

“…Additionally microglial cell induction of inflammosomes (innate immune response protein complexes that respond to pathogen associated molecular patterns) is precipitated during acute lentiviral infection, and inflammosome activation associates with brain pathology in a feline immunodeficiency model of HIV encephalitis [52]. Finally, HIV-Tat protein may be a direct trigger or in a pathway associated with processes leading to microglial activation, though the extent to which this is an important cause of ongoing activation in latent cART treated infection is unclear [53, 54]. Overall, this new understanding of the homeostasis and behavior of microglia supports their major role in contributing to the problem of persistent CNS immune activation in HIV: microglia respond to acute HIV in an immediate and dynamic fashion, and once perturbed they are resident cells of the CNS that may harbor integrated HIV long-term, associated with constant cellular immune activation.…”

Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection

“…Additionally, YY1 was reported to suppress the replication of some viruses, such as human immunodeficiency virus type I, hepatitis B virus, and Rift Valley fever virus [19, 34, 35]. The roles of YY1 in the induction of IFN-1 production and signaling during viral infection remain to be elucidated.…”

“…One of key transcription factors binding to IFN-β promoter is Yin Yang 1 (YY1), which binds to the murine IFN-β promoter and regulates its transcriptional capacity [17, 18]. YY1, a ubiquitous, highly conserved zinc finger transcription factor, functions to either activate or repress expression through directly binding to a consensus element in the promoters of a high number of genes, including c-Myc, c-Fos , β-casein, human immunodeficiency virus type I, and several other cellular or viral genes [19-22]. Furthermore, YY1 interacts with co-activators and co-repressors, which modulate its regulatory behavior [23, 24].…”