Inhibition of Natural Killer Cell–Mediated Cytotoxicity by Kaposi's Sarcoma–Associated Herpesvirus K5 Protein

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) K3 and K5 proteins dramatically downregulate MHC class I molecules. However, although MHC class I downregulation may protect KSHV-infected cells from cytotoxic T lymphocyte recognition, these cells become potential targets for natural killer (NK) cell-mediated lysis. We now show that K5 also downregulates ICAM-1 and B7-2, which are ligands for NK cell-mediated cytotoxicity receptors. As a consequence, K5 expression drastically inhibits NK cell-mediated cytotoxicity. Conversely, de novo expression of B7-2 and ICAM-1 resensitizes the K5-expressing cells to NK cell-mediated cytotoxicity. This is a novel viral immune evasion strategy where KSHV K5 achieves immune avoidance by downregulation of cellular ligands for NK cell-mediated cytotoxicity receptors.

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

“…115 The K5 protein encoded by HHV-8 drastically inhibits NK cell-mediated cytotoxicity by downregulating ICAM-1 and B7-2 that represent ligands of NK cell-mediated lysis. 116,117 The HCV envelope protein E2 can inhibit and crosslink CD81 on lymphocytes blocking both cytotoxicity and IFN-g production mediated by NK cells. 118 In case of HIV, infected cells escape CTL attack by downregulation of HLA-A and HLA-B antigens, but not of HLA-C and HLA-E antigens on the cell surface.…”

Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity

“…Previous experiments to assess the potential role of K5 in protecting cells from NK-mediated cytotoxicity led to contra- dictory results, due in part to the use of NK cell lines that may not be representative of killing by primary human NK cells (3,28). By identifying MICA/B as targets of K5, we provide evidence that K5 expression can protect cells from NKG2D-mediated NK cytotoxicity, independent of its effect on other surface receptors such as ICAM-1.…”

“…NK cell activity is controlled by a balance of inhibitory and activatory signals received through cell surface receptors. KSHV down-regulates surface MHC class I molecules via the K3 and K5 immune evasion genes, which encode viral E3 ligases that target MHC class I alleles for ubiquitylation and lysosomal degradation (2)(3)(4). This reduction in MHC class I expression may render KSHV-infected cells susceptible to NK cell killing.…”

Protéines Nef du VIH et K3/K5 du virus associé au sarcoma de Kaposi : des « parasites »de la voie d’endocytose

“…À l'opposé, seule l'expression de K5 module l'expression de B7.2 et d'ICAM-1. Ces diffé-rences de spécificité semblent passer par une interaction entre les régions trans-membranaires de K3 et K5 et celles des protéines cibles [26][27][28]. Le virus murin homologue de KSHV, MHV-68, module aussi l'expression de surface du CMH-I par l'intermédiaire de protéines semblables à K3 et K5 (MK3 et MK5) responsables de l'ubiquitinylation des molécules de classe I murines.…”