HIV-1 Nef-mediated downregulation of CD155 results in viral restriction by KIR2DL5+ NK cells

Abstract

Antiviral NK cell activity is regulated through the interaction of activating and inhibitory NK cell receptors with their ligands on infected cells. HLA class I molecules serve as ligands for most killer cell immunoglobulin-like receptors (KIRs), but no HLA class I ligands for the inhibitory NK cell receptor KIR2DL5 have been identified to date. Using a NK cell receptor/ligand screening approach, we observed no strong binding of KIR2DL5 to HLA class I or class II molecules, but confirmed that KIR2DL5 binds to the poliovirus receptor (PVR, CD155). Functional studies using primary human NK cells revealed a significantly decreased degranulation of KIR2DL5⁺ NK cells in response to CD155-expressing target cells. We subsequently investigated the role of KIR2DL5/CD155 interactions in HIV-1 infection, and showed that multiple HIV-1 strains significantly decreased CD155 expression levels on HIV-1-infected primary human CD4⁺ T cells via a Nef-dependent mechanism. Co-culture of NK cells with HIV-1-infected CD4⁺ T cells revealed enhanced anti-viral activity of KIR2DL5⁺ NK cells against wild-type versus Nef-deficient viruses, indicating that HIV-1-mediated downregulation of CD155 renders infected cells more susceptible to recognition by KIR2DL5⁺ NK cells. These data show that CD155 suppresses the antiviral activity of KIR2DL5⁺ NK cells and is downmodulated by HIV-1 Nef protein as potential trade-off counteracting activating NK cell ligands, demonstrating the ability of NK cells to counteract immune escape mechanisms employed by HIV-1. HIV infection remains a global health emergency that has caused around 36 million deaths. NK cells play an important role in the control of HIV-1 infections, and are able to detect and destroy infected cells using a large array of activating and inhibitory receptors, including KIRs. Here we demonstrate that CD155 serves as a functional interaction partner for the inhibitory NK cell receptor KIR2DL5, and that KIR2DL5⁺ NK cells are inhibited by CD155-expressing target cells. CD155 surface expression on HIV-1-infected CD4⁺ T cells was downregulated by the HIV-1 Nef protein, resulting in increased anti-viral activity of KIR2DL5⁺ NK cells through the loss of inhibitory signals. Taken together, these studies demonstrate functional consequences of the novel interaction between KIR2DL5 and CD155 for the antiviral activity of KIR2DL5⁺ NK cells during HIV-1 infection.