Human X‐DING‐CD4 mediates resistance to HIV‐1 infection through novel paracrine‐like signaling

Abstract

X-DING-CD4 is a novel phosphatase mediating antiviral responses to HIV-1 infection. This protein is constitutively expressed and secreted by HIV-1 resistant CD4+ T cells and its mRNA transcription is up-regulated in PBMCs from HIV-1 elite controllers. The secreted/soluble X-DING-CD4 protein form is of particular importance because it blocks virus transcription when added to HIV-1 susceptible cells. Our research aimed to determine the contribution of this factor to induction of antiviral response in target cells. We found that soluble X-DING-CD4 enters cells by endocytosis and influx of this protein induced transcription of IFN-α and endogenous X-DING-CD4 mRNA in transformed CD4+ T cells and primary macrophages. Treatment of HIV-1 susceptible cells with exogenous X-DING-CD4 caused depletion of phosphorylated p50 and p65 NF-κB subunits and a significant reduction in p50/p65 NF-κB binding to the HIV-1 LTR. Together, these findings indicate a novel antiviral mechanism mediated by the influx of soluble X-DING-CD4, its signaling to promote self-amplification and functional duality as an endogenous innate immunity effector and exogenous factor regulating gene expression in bystander cells.

DING Protein Inhibits Transcription of HIV-1 Gene through Suppression of Phosphorylation of NF-κB p65

“…Importantly, p65 co-factor, p50 was also dephosphorylated by DING. This result aligned with the previously published data, indicate depletion of the phosphorylated forms of p65- and p50-NF-κB in nuclei of 1G5 cells treated with the exogenous human variant of DING protein [ 56 ]. The current study provided additional information indicating that that the mechanism of inactivation of NF-κB complex by DING p27SJ was I-κB independent.…”

Improving combination antiretroviral therapy by targeting HIV-1 gene transcription

“…This protein also suppresses HIV-1 transcription and replication in microglial cells. The inhibition of the interaction between NF-KB and the HIV-1 promoter DING proteins is a common mechanism of action of all these DING proteins [142,143] that could also be used to treat chronic inflammation leading to non-AIDS events [144,145]. As suggested for X-DING-CD4 [129], their functions could also uncover a role in the innate response to infections including HIV-1 [146].…”

Untitled

“…La caractérisation d'une autre protéine DING chez les plantes provient d'une étude réalisée chez le millepertuis (Hypericum perforatum) (Darbinian-Sarkissian et al, 2006) (Darbinian-Sarkissian et al, 2006 ;Darbinian et al, 2008Darbinian et al, , 2011. Des protéines DING bactériennes et humaines bloquent également la transcription du virus de l'immunodéficience humaine HIV-1 (Cherrier et al, 2011 ;Sachdeva et al, 2013Sachdeva et al, , 2015Suh et al, 2013). De plus, des patients infectés par le HIV réagissent à l'infection en sur-accumulant les protéines DING humaines dans le sérum .…”