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Vol. 14, Issue 12, 4857-4870, December 2003

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Human Immunodeficiency Virus-1 Nef Expression Induces Intracellular Accumulation of Multivesicular Bodies and Major Histocompatibility Complex Class II Complexes: Potential Role of Phosphatidylinositol 3-Kinase

Pamela Stumptner-Cuvelette ^*, Mabel Jouve, Julie Helft, Marc Dugast, Anne-Sophie Glouzman , Karin Jooss , Graça Raposo , and Philippe Benaroch ^* 

^* Institut National de la Santé et de la Recherche Médicale U520, Institut Curie, Section de recherche. 75005 Paris, France; Centre National de la Recherche Scientifique Unité Mixte Recherche 144, Institut Curie, Section de recherche. 75005 Paris, France; and Genethon III, 91002 Evry, France

Submitted April 8, 2003; Revised August 1, 2003; Accepted August 22, 2003
Monitoring Editor: Juan Bonifacino

Nef alters the cell surface expression of several immunoreceptors, which may contribute to viral escape. We show that Nef modifies major histocompatibility complex class II (MHC II) intracellular trafficking and thereby its function. In the presence of Nef, mature, peptide-loaded MHC II were down-modulated at the cell surface and accumulated intracellularly, whereas immature (invariant [Ii] chain-associated) MHC II expression at the plasma membrane was increased. Antibody internalization experiments and subcellular fractionation analyses showed that immature MHC II were internalized from the plasma membrane but had limited access to lysosomes, explaining the reduced Ii chain degradation. Immunoelectron microscopy revealed that Nef expression induced a marked accumulation of multivesicular bodies (MVBs) containing Nef, MHC II, and high amounts of Ii chain. The Nef-induced up-regulation of surface Ii chain was inhibited by LY294002 exposure, indicating the involvement of a phosphatidylinositol 3-kinase, whose products play a key role in MVB biogenesis. Together, our results indicate that Nef induces an increase of the number of MVBs where MHC II complexes accumulate. Given that human immunodeficiency virus recruits the MVB machinery for its assembly process, our data raise the possibility that Nef is involved in viral assembly through its effect on MVBs.

Abbreviations used: EM, electron microscopy; HA, hemagglutinin; Ii, Ii chain; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; MVB, multivesicular body; PI 3-kinase, phosphatidylinositol 3-kinase; TfR, transferrin receptor; TGN, trans-Golgi network.

Corresponding author. E-mail address: benaroch{at}curie.fr or graposo{at}curie.fr.

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