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

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.