title: 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.
abstract: The human immunodeficiency virus type 1 (HIV-1) vpu gene encodes a small integral membrane phosphoprotein with two established functions: degradation 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 responsible for the previously observed decrease in the expression of major histocompatibility complex (MHC) class I molecules on the surface of HIV-1-infected cells. Cells infected with HIV-1 isolates that fail to express Vpu, or that express genetically modified forms of Vpu that no longer induce CD4 degradation, exhibit little downregulation of MHC class I molecules. The effect of Vpu on class I biogenesis was analyzed in more detail using a Vpu-expressing recombinant vaccinia virus (VV). VV-expressed Vpu induces the rapid loss of newly synthesized endogenous or VV-expressed class I heavy chains in the ER, detectable either biochemically or by reduced cell surface expression. This effect is of similar rapidity and magnitude as the VV-expressed Vpu-induced degradation of CD4. Vpu had no discernible effects on cell surface expression of VV-expressed mouse CD54, demonstrating the selectivity of its effects on CD4 and class I heavy chains. VV-expressed Vpu does not detectably affect class I molecules that have been exported from the ER. The detrimental effects of Vpu on class I molecules could be distinguished from those caused by VV-expressed herpes virus protein ICP47, which acts by decreasing the supply of cytosolic peptides to class I molecules, indicating that Vpu functions in a distinct manner from ICP47. Based on these findings, we propose that Vpu-induced downregulation of class I molecules may be an important factor in the evolutionary selection of the HIV-1-specific vpu gene by contributing to the inability of CD8+ T cells to eradicate HIV-1 from infected individuals.
authors.affiliation: Institute of Virology and Immunobiology, University of Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kerkau
authors.forename: I
authors.initials: I
authors.lastname: Bacik
authors.forename: J R
authors.initials: JR
authors.lastname: Bennink
authors.forename: J W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: T
authors.initials: T
authors.lastname: Húnig
authors.forename: A
authors.initials: A
authors.lastname: Schimpl
authors.forename: U
authors.initials: U
authors.lastname: Schubert
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015536:Down-Regulation; D015497:HIV-1 / Q000276:immunology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D015395:Histocompatibility Antigens Class I; D054298:Human Immunodeficiency Virus Proteins; D017874:Immediate-Early Proteins; D011994:Recombinant Proteins; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins