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By
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From the * Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany;
the 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. VVexpressed 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.
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda,
Maryland 20892; and the § Laboratory of Molecular Microbiology, National Institute of Allergy and
Infectious Diseases, Bethesda, Maryland 20892
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