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 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 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 ce...

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Main Authors: Kerkau, Thomas, Bacik, Igor, Bennink, Jack R., Yewdell, Jonathan W., Hünig, Thomas, Schimpl, Anneliese, Schubert, Ulrich
Format: Online
Language:English
Published: The Rockefeller University Press 1997
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196253/
id pubmed-2196253
recordtype oai_dc
spelling pubmed-21962532008-04-16 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 Kerkau, Thomas Bacik, Igor Bennink, Jack R. Yewdell, Jonathan W. Hünig, Thomas Schimpl, Anneliese Schubert, Ulrich Article 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. The Rockefeller University Press 1997-04-07 /pmc/articles/PMC2196253/ /pubmed/9104816 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Kerkau, Thomas
Bacik, Igor
Bennink, Jack R.
Yewdell, Jonathan W.
Hünig, Thomas
Schimpl, Anneliese
Schubert, Ulrich
spellingShingle Kerkau, Thomas
Bacik, Igor
Bennink, Jack R.
Yewdell, Jonathan W.
Hünig, Thomas
Schimpl, Anneliese
Schubert, Ulrich
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
author_facet Kerkau, Thomas
Bacik, Igor
Bennink, Jack R.
Yewdell, Jonathan W.
Hünig, Thomas
Schimpl, Anneliese
Schubert, Ulrich
author_sort Kerkau, Thomas
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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
description 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.
publisher The Rockefeller University Press
publishDate 1997
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196253/
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