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

TY - JOUR

T1 - HIV-1 Nef-mediated downregulation of CD155 results in viral restriction by KIR2DL5+ NK cells

AU - Fittje, Pia

AU - Hölzemer, Angelique

AU - Garcia-Beltran, Wilfredo F

AU - Vollmers, Sarah

AU - Niehrs, Annika

AU - Hagemann, Kerri

AU - Martrus, Glòria

AU - Körner, Christian

AU - Kirchhoff, Frank

AU - Sauter, Daniel

AU - Altfeld, Marcus

PY - 2022/6

Y1 - 2022/6

N2 - 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.

AB - 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.

KW - Antiviral Agents/metabolism

KW - Down-Regulation

KW - HIV Infections

KW - HIV Seropositivity

KW - HIV-1

KW - Humans

KW - Killer Cells, Natural

KW - Ligands

KW - Receptors, Natural Killer Cell/metabolism

KW - Receptors, Virus

KW - nef Gene Products, Human Immunodeficiency Virus/genetics

U2 - 10.1371/journal.ppat.1010572

DO - 10.1371/journal.ppat.1010572

M3 - SCORING: Journal article

C2 - 35749424

VL - 18

JO - PLOS PATHOG

JF - PLOS PATHOG

SN - 1553-7366

IS - 6

M1 - e1010572

ER -