Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains
Journal of Virology
Reduction of major histocompatibility complex class I cell surface expression occurs in adenovirus-, herpes simplex virus-, human cytomegalovirus (HCMV)-, and murine cytomegalovirus-infected cell systems. Recently, it was demonstrated that the down-regulation mediated by HCMV infection is posttranslational, as a result of increased turnover of class I heavy chains in the endoplasmic reticulum (M. To identify HCMV genes involved in class I regulation, we screened our bank of HCMV deletion
... for this phenotype. A mutant with a 9-kb deletion in the S component of the HCMV genome (including open reading frames IRS1 to US9 and US11) failed to down-regulate class I heavy chains. By examining the effects of smaller deletions within this portion of the HCMV genome, a 7-kb region containing at least nine open reading frames was shown to contain the genes required for reduction in heavy-chain expression. Furthermore, it was determined that at least two independent loci within the 7-kb region were able to cause class I heavy-chain down-regulation. One of these, US11, encodes a 32-kDa glycoprotein which causes down-regulation of class I heavy chains in the absence of other viral gene products. Hence, a specific function associated with a phenotype of the HCMV replicative cycle has been mapped to a dispensable gene region. These loci may be important for evasion of the host's immune response and viral persistence. on May 9, 2020 by guest http://jvi.asm.org/ Downloaded from 4834 JONES ET AL. J. VIROL. on May 9, 2020 by guest http://jvi.asm.org/ Downloaded from VOL. 69, 1995 CLASS I HEAVY-CHAIN DOWN-REGULATION BY HCMV US11 4835 on May 9, 2020 by guest http://jvi.asm.org/ Downloaded from FIG. 4. Summary of MHC class I heavy-chain expression data from HFF cells infected with wild-type and mutant HCMV. ( A) The first line shows the overall organization of the HCMV wild-type (WT) genome, and the second line is an expansion of the wild-type HindIII-Q and -X regions of the S component. The ORFs are indicated by unshaded rectangles; the unlabeled ORF overlapping US4 and US5 is US4.5. The locations of the loci which contain genes which are sufficient for MHC class I heavy-chain down-regulation are shown. One locus contains ORFs US2 to US5 (bases 193119 to 195607), and the other locus contains ORFs US10 and US11 (bases 199083 to 200360). (B to D) The deletions within the various HCMV mutants are indicated by shaded rectangles. (B) RV670 is deleted of IRS1 to US9 and US11, RV35 is deleted of US6 to US11, RV67 is deleted of US10 and US11, RV80 is deleted of US8 and US9, RV725 is deleted of US7, RV69 is deleted of US6, RV47 is deleted of US2 and US3, RV5122 is deleted of US1, RV46 is deleted of IRS1, and RV7186 is deleted of IRS1 to US11. (C) RV798 is deleted of IRS1 to US6. (D) RV7119 is deleted of US2 to US10. MHC class I heavy-chain down-regulation results are from immunoprecipitation experiments (using the heavy-chain conformation-independent monoclonal antibody, TP25.99) in which HCMV-infected HFF cells were radiolabeled at late times postinfection. 4836 JONES ET AL. J. VIROL.