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

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 peripheral blood mononuclear cells 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. The present study aimed to determine the contribution of this factor to the induction of the antiviral response in target cells. We found that soluble X-DING-CD4 enters cells by endocytosis and that influx of this protein induced transcription of interferon-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 nuclear factor kappa β subunits and a significant reduction in p50/p65 nuclear factor kappa β binding to the HIV-1 long terminal repeat. Taken 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.