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Journal of Virology, August 2008, p. 7758-7767, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.02668-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Competition Model for Upregulation of the Major Histocompatibility Complex Class II-Associated Invariant Chain by Human Immunodeficiency Virus Type 1 Nef{triangledown}

Richard S. Mitchell,1* Rittik Chaudhuri,2 O. Wolf Lindwasser,2 Kristie A. Tanaka,1 David Lau,3 Rudy Murillo,1 Juan S. Bonifacino,2 and John C. Guatelli1,4

Department of Medicine,1 Division of Biology, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093,3 Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,2 San Diego Veterans Affairs Healthcare System, 3350 La Jolla Village Dr., San Diego, California 921214

Received 16 December 2007/ Accepted 12 May 2008

The human immunodeficiency virus type 1 (HIV-1) Nef protein upregulates the expression of the invariant chain (Ii)/major histocompatibility complex class II (MHC-II) complex at the cell surface. This complex appears to reach the antigen-loading endosomal compartment at least in part via an indirect pathway in which it is internalized from the cell surface via the adaptor protein 2 (AP-2) complex. Here we provide evidence for a competition model to explain how Nef upregulates the expression of Ii at the cell surface. In this model, Nef and Ii compete for binding to AP-2. In support of this model, Nef decreased the rate of internalization of Ii from the cell surface. The AP-binding dileucine motif in Nef, ENTSLL165, was necessary and sufficient for the upregulation of Ii. In addition, two leucine-based AP-binding motifs in the Ii cytoplasmic tail, DDQRDLI8 and EQLPML17, were critical for the efficient upregulation of Ii by Nef. Experiments using Nef variants in which the native dileucine-based sorting motif was replaced with similar motifs from cellular transmembrane proteins allowed modulation of AP-binding specificity. Analysis of these variants suggested that the binding of Nef to AP-2 is sufficient to upregulate Ii at the plasma membrane. Finally, interference with the expression of AP-2 caused an upregulation of Ii at the plasma membrane, and this decreased the effect of Nef. These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II.

* Corresponding author. Mailing address: University of California, San Diego, 9500 Gilman Dr., SCRB Rm. 303, La Jolla, CA 92093-0679. Phone: (858) 552-8585, ext. 7203. Fax: (858) 552-7445. E-mail: rsmitchell{at}ucsd.edu

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 7758-7767, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.02668-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chaudhuri, R., Mattera, R., Lindwasser, O. W., Robinson, M. S., Bonifacino, J. S. (2009). A Basic Patch on {alpha}-Adaptin Is Required for Binding of Human Immunodeficiency Virus Type 1 Nef and Cooperative Assembly of a CD4-Nef-AP-2 Complex. J. Virol. 83: 2518-2530 [Abstract] [Full Text]  
  • Toussaint, H., Gobert, F.-X., Schindler, M., Banning, C., Kozik, P., Jouve, M., Kirchhoff, F., Benaroch, P. (2008). Human Immunodeficiency Virus Type 1 Nef Expression Prevents AP-2-Mediated Internalization of the Major Histocompatibility Complex Class II-Associated Invariant Chain. J. Virol. 82: 8373-8382 [Abstract] [Full Text]  


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