THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) VPU PROTEIN INTERFERES WITH AN EARLY STEP IN THE BIOSYNTHESIS OF MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS-I MOLECULES

The human immunodeficiency virus type 1 (HIV-1) vpu gene encodes a sma ll integral membrane phosphoprotein with two established functions. de gradation of the viral coreceptor CD4 in the endoplasmic reticulum (ER ) and augmentation of virus particle release from the plasma membrane of HIV-1-infected cells. We show here that Vpu is also largely respons ible for the previously observed decrease in the expression of major h istocompatibility complex (MHC) class I molecules on the surface of HI V-1-infected cells. Cells infected with HIV-1 isolates that fail to ex press Vpu, or that express genetically modified forms of Vpu that no l onger induce CD4 degradation, exhibit little downregulation of MHC cla ss I molecules. The effect of Vpu on class I biogenesis was analyzed i n more detail using a Vpu-expressing recombinant vaccinia virus (VV), VV-expressed Vpu induces the rapid loss of newly synthesized endogenou s or VV-expressed class I heavy chains in the ER, detectable either bi ochemically or by reduced cell surface expression. This effect is of s imilar rapidity and magnitude as the VV-expressed Vpu-induced degradat ion of CD4. Vpu had no discernible effects on cell surface expression of VV-expressed mouse CD54, demonstrating the selectivity of its effec ts on CD4 and class I heavy chains. VV-expressed Vpu does not detectab ly affect class I molecules that have been exported from the ER. The d etrimental effects of Vpu on class I molecules could be distinguished from those caused by VV-expressed herpes virus protein ICP47, which ac ts by decreasing the supply of cytosolic peptides to class I molecules , indicating that Vpu functions in a distinct manner from 1CP47. Based on these findings, we propose that Vpu-induced downregulation of clas s I molecules may be an important factor in the evolutionary selection of the HIV-1-specific vpu gene by contributing to the inability of CD 8(+) T cells to eradicate HIV-1 from infected individuals.