The T-cell-mediated immune response plays a central role in the defense against intracellular pathogens. To avoid this immune response, viruses have evolved elaborate mechanisms that target and modulate many different aspects of the host's immune system. A target common to many of these viruses is the major histocompatibility complex (MHC) class I molecules. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes K3 and K5 zinc finger membrane proteins which remove MHC class I molecules from the cell surface. K3 and K5 exhibit 40% amino acid identity to each other and localize primarily near the plasma membrane. While K3 and K5 dramatically downregulated class I molecules, they displayed different specificities in downregulation of HLA allotypes. K5 significantly downregulated HLA-A and -B and downregulated HLA-C only weakly, but not HLA-E, whereas K3 downregulated all four HLA allotypes. This selective downregulation of HLA allotypes by K5 was partly due to differences in amino acid sequences in their transmembrane regions. Biochemical analyses demonstrated that while K3 and K5 did not affect expression and intracellular transport of class I molecules, their expression induced rapid endocytosis of the molecules. These results demonstrate that KSHV has evolved a novel immune evasion mechanism by harboring similar but distinct genes, K3 and K5, which target MHC class I molecules in different ways.A major immune defense against viral infection is mediated by cytotoxic T lymphocytes (CTLs), which recognize and lyse infected cells upon engagement of the T-cell receptor with major histocompatibility complex (MHC) class I molecules presenting viral peptides (10, 26). Viral proteins are degraded to peptides by the proteasomes in the cytosol. These peptides are translocated by the transporter associated with antigen processing (TAP) to the endoplasmic reticulum (ER), where they assemble with the MHC class I heavy chain and ␤2 microglobulin to form a trimeric complex. This mature complex is then transported from the ER to the plasma membrane, where the MHC class I complexes present the peptide to CTLs (20,35).Herpesviruses establish lifelong infections despite the presence of an active immune system. To achieve this, herpesviruses encode gene products that affect MHC class I expression, either at the level of transcription or of expression at the cell surface (26). For example, the herpes simplex virus type 1 US12 gene product, called ICP47, binds to TAP and prevents the delivery of cytosolic antigen peptides to assembling class I molecules in the ER (7, 11, 37). Epstein-Barr virus-encoded EBNA-1 protein inhibits antigen processing, thus affecting presentation of certain peptides by MHC class I complexes (18). Human cytomegalovirus (HCMV) and murine CMV contain numerous lytic glycoproteins, each of which is sufficient to cause increased turnover of MHC class I molecules. Two ERresident glycoproteins, US2 and US11, of HCMV are sufficient to induce the rapid dislocation of newly synthesized MHC class I proteins from the ER ...

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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.