Downregulation of major histocompatibility complex class I molecules by Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins

The T-cell-mediated immune response plays a central role in the defense aga inst intracellular pathogens. To avoid this immune response, viruses have e volved elaborate mechanisms that target and modulate many different aspects of the host's immune system. A target common to many of these viruses is t he major histocompatibility complex (MHC) class I molecules. Kaposi's sarco ma-associated herpesvirus (KSHV) encodes K3 and K5 zinc finger membrane pro teins which remove MHC class I molecules from the cell surface. K3 and K5 e xhibit 40% amino acid identity to each other and Localize primarily near th e plasma membrane. While K3 and K5 dramatically downregulated class I molec ules, they displayed different specificities in downregulation of HLA allot ypes. K5 significantly downregulated HLA-A and -B and downregulated HLA-C o nly weakly, but not HLA-E, whereas K3 downregulated all four HLA allotypes. This selective downregulation of If LA allotypes by K5 was partly due to d ifferences in amino acid sequences in their transmembrane regions. Biochemi cal analyses demonstrated that while K3 and K5 did not affect expression an d intracellular transport of class I molecules, their expression induced ra pid endocytosis of the molecules. These results demonstrate that KSHV has e volved a novel immune evasion mechanism by harboring similar but distinct g enes, K3 and K5, which target MHC class I molecules in different ways.