The Journal of Experimental Medicine
for flow cytometry > invitrogen
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 391K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kerkau, T.
Right arrow Articles by Schubert, U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kerkau, T.
Right arrow Articles by Schubert, U.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/1997/4/1295/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1295-1306

Article

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

Thomas Kerkau*, Igor Bacik{ddagger}, Jack R. Bennink{ddagger}, Jonathan W. Yewdell{ddagger}, Thomas Hünig*, Anneliese Schimpl*, and Ulrich Schubert{ddagger},§

From the * Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany; the {ddagger} 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

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.

Address correspondence to Ulrich Schubert, Laboratory of Viral Diseases, NIAID, NIH, 4/213, 9000 Rockville Pike, Bethesda, MD 20892-0440.

We are indebted to Malcolm A. Martin and Klaus Strebel for support, and we thank Dinah S. Singer, Klaus Strebel, Gustav Russ, Heidi Link Snyder, and Luis Anton for critical comments on the manuscript. We are grateful to Randy R. Brutkiewicz for technical advice on FACS® analysis. We thank E.A. Berger for rVV vCB-3, W. Sebald for providing of rIl-2, H. Rübsamen-Waigmann for HIV-2D205, and G. Hunsmann for SIVmac. We thank Raymond Sweet for anti-CD4 antiserum, Tomas Porstmann (SERAMUN GmbH, Berlin, FRG) for anti-Vpu serum (sheep), Kim Hasenkrug for mAb 215, and Klaus Strebel for anti-Vpu serum (rabbit). We thank G. Kober for excellent technical assistance and O. Kutsch for the preparation and titration of virus stocks.

1Abbreviations used in this paper: β2m, β2-microglobulin; CHAPS, 3-(3cholamidopropyl)diethylammonio-1 propane sulfonate; ER, endoplasmic reticulum; pAbs-ex8, exon 8–specific polyclonal antibodies; rVV, recombinant VV; SIV, simian immunodeficiency virus; TAP, transporter associated with antigen presentation; TCD8+, CD8+ T cells; VV, vaccinia virus.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS