Abstract
Background Human cells may respond to viral infection or other stress by expressing on their membrane ligands for activating receptors present on cytotoxic NK and T cells, such as NKG2D and DNAM-1 receptors, thus eliciting recognition and elimination by the immune system. Work from our laboratory has shown that, upon infection with HIV-1, CD4 T cells over-express ligands for NKG2D (MICA/B and ULBP2) and DNAM-1 (PVR), hence becoming susceptible to NKG2D-and DNAM-1-mediated lysis by NK cells. The cell-surface expression of activating ligands, however, is down-regulated by the HIV-1 Nef and Vpu proteins, a phenomenon that protects infected cells from cytotoxic responses to some extent. Here we further investigated the dual regulation of activating ligands by HIV-1 focusing on viral and cellular factors involved in up-regulation of ligands expression and on the capacity of HIV-infected cells to release soluble ligands in the extracellular environment.
Highlights
Human cells may respond to viral infection or other stress by expressing on their membrane ligands for activating receptors present on cytotoxic NK and T cells, such as NKG2D and DNAM-1 receptors, eliciting recognition and elimination by the immune system
Results showed that the HIV-1 Vpr protein increases cell-surface and total PVR levels acting at a post-transcriptional level
As reported previously for NKG2D ligands, PVR was up-regulated by Vpr via activation of the ATR kinase that triggers the DNA Damage Response (DDR) pathway and G2 arrest
Summary
Human cells may respond to viral infection or other stress by expressing on their membrane ligands for activating receptors present on cytotoxic NK and T cells, such as NKG2D and DNAM-1 receptors, eliciting recognition and elimination by the immune system. Work from our laboratory has shown that, upon infection with HIV-1, CD4+ T cells over-express ligands for NKG2D (MICA/B and ULBP2) and DNAM-1 (PVR), becoming susceptible to NKG2D-and DNAM-1-mediated lysis by NK cells. The cell-surface expression of activating ligands, is down-regulated by the HIV-1 Nef and Vpu proteins, a phenomenon that protects infected cells from cytotoxic responses to some extent. We further investigated the dual regulation of activating ligands by HIV-1 focusing on viral and cellular factors involved in up-regulation of ligands expression and on the capacity of HIV-infected cells to release soluble ligands in the extracellular environment.
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