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Journal of Virology, September 2008, p. 8373-8382, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00670-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Nef Expression Prevents AP-2-Mediated Internalization of the Major Histocompatibility Complex Class II-Associated Invariant Chain ^,

Hélène Toussaint,^1,2 François-Xavier Gobert,^1,2 Michael Schindler,³ Carina Banning,³ Patrycja Kozik,⁴ Mabel Jouve,^1,2 Frank Kirchhoff,⁵ and Philippe Benaroch^1,2*

Institut Curie, Centre de Recherche, Paris F-75248, France,¹ INSERM U653, F-75248 Paris Cedex 05, France,² Heinrich-Pette-Institut, 20251 Hamburg, Germany,³ University of Cambridge, Cambridge CB2 0XY, United Kingdom,⁴ Abteilung Virologie-Universitatsklinikum, 89081 Ulm, Germany⁵

Received 26 March 2008/ Accepted 10 June 2008

The lentiviral Nef protein has been studied extensively for its ability to induce the downregulation of several immunoreceptors on the surfaces of infected cells. However, Nef expression is unique in inducing highly effective upregulation of the major histocompatibility complex class II-associated chaperone invariant (Ii) chain complexes in different cell types. Under normal conditions, endocytosis of the Ii chain and other molecules, like the transferrin receptor and CD4, is rapid and AP-2 dependent. Human immunodeficiency virus type 1 (HIV-1) Nef expression strongly reduces the internalization of the Ii chain, enhances that of CD4, and does not modify transferrin uptake. The mutation of AP-2 binding motifs LL164 and DD174 in Nef leads to the inhibition of Ii chain upregulation. In AP-2-depleted cells, surface levels of the Ii chain are high and remain unmodified by Nef expression, further indicating that Nef regulates Ii chain internalization via the AP-2 pathway. Immunoprecipitation experiments revealed that the Ii chain can interact with Nef in a dileucine-dependent manner. Importantly, we have shown that Nef-induced CD4 downregulation and Ii chain upregulation are genetically distinguishable. We have identified natural nef alleles that have lost one of the two functions but not the other one. Moreover, we have characterized Nef mutant forms possessing a similar phenotype in the context of HIV-1 infection. Therefore, the Nef-induced accumulation of Ii chain complexes at the cell surface probably results from a complex mechanism leading to the impairment of AP-2-mediated endocytosis rather than from direct competition between Nef and the Ii chain for binding AP-2.

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* Corresponding author. Mailing address: Institut Curie INSERM U653, 26 rue d'Ulm, 75248 Paris Cedex 05, France. Phone: 331 4234 6432. Fax: 331 4234 6438. E-mail: benaroch{at}curie.fr

Published ahead of print on 2 July 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, September 2008, p. 8373-8382, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00670-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.