Downregulation of Major Histocompatibility Complex Class I Molecules by Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Proteins

Abstract

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 ...

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

“…98 In addition, the KSHVencoded K3 and K5 proteins also differentially affect MHC class I antigen expression: the K3 protein significantly downregulates HLA-A, -B, -C and -E antigens, whereas the K5 protein selectively suppresses the expression of HLA-A and -B, but not that of HLA-E antigens. 99 This difference is attributable to altered amino acid sequences in the transmembrane region of the respective HLA class I antigens. 71 Recently, it has been shown that the HPV E5 protein specifically downregulates HLA-A and -B gene transcription.…”

Inhibition of MHC Class II Expression and Immune Responses by c-MIR

“…MIR family proteins bind to the membrane through their hydrophobic domains located at the center and possess two intracellular regions. The initially discovered MIR family proteins are viral E3s: MIR1 and MIR2 of Kaposi's sarcoma-associated herpesvirus (KSHV), mK3 of murine ␥-herpesvirus 68, and m153R of myxomavirus (3,(5)(6)(7)(8)(9). Each molecule targets a different set of Ag presentation-related molecules: CD1d and MHC class I (MHC I) for MIR1; B7-2, ICAM-1, CD1d, and MHC I for MIR2; MHC I for mK3; MHC I, CD4, and Fas for m153R (3, 5, 9 -12).…”

Regulation of CD1d expression and function by a herpesvirus infection

“…They function as membrane-bound ubiquitin ligases, leading to ubiquitination of their target proteins on lysine residues in their cytosolic tails (32). The result of this ubiquitination is the enhancement of the endocytosis of the target chain and its delivery (via the multivesicular body) to the lysosome, where it is proteolytically destroyed (28,30). Both MIR1 and MIR2 reduce the cell surface levels of MHC class I; MIR2 also selectively targets the costimulatory molecules B7.2 and ICAM-1, both of which are involved in the enhancement of helper T cell signaling (33,34).…”

“…[25][26][27]. Like other herpesvirus family members, it encodes proteins that block MHC class I expression on the cell surface (28)(29)(30)(31). These are known as modulator of immune recognition (MIR) proteins; MIR1 and MIR2 are expressed during lytic replication and are encoded by the open reading frames K3 and K5, respectively.…”