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Journal of Virology, October 2000, p. 9256-9266, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Distinct Trafficking Pathways Mediate Nef-Induced and Clathrin-Dependent Major Histocompatibility Complex Class I Down-Regulation

Sylvie Le Gall,1 Florence Buseyne,2 Alicja Trocha,3 Bruce D. Walker,3 Jean-Michel Heard,1 and Olivier Schwartz1,*

Unité Rétrovirus et Transfert Génétique, URA CNRS 1930,1 and Laboratoire d'Immunopathologie Virale,2 Institut Pasteur, 75724 Paris Cedex 15, France, and Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 021293

Received 22 February 2000/Accepted 11 July 2000

The human immunodeficiency virus type 1 Nef protein alters the post-Golgi stages of major histocompatibility complex class I (MHC-I) biogenesis. Presumed mechanisms involve the disclosure of a cryptic tyrosine-based sorting signal (YSQA) located in the cytoplasmic tail of HLA-A and -B heavy chains. We changed this signal for a prototypic sorting motif (YSQI or YSQL). Modified HLA-A2 molecules, termed A2-endo, displayed constitutively low surface levels and accumulated in a region close to or within the Golgi apparatus, a behavior reminiscent of wild-type HLA-A2 in Nef-expressing cells. However, several lines of evidence indicate that the action of prototypic signals on MHC-I trafficking differs from that of Nef. Internalization of surface A2-endo was more rapid and was associated with efficient recycling to the surface. A transdominant-negative mutant of dynamin-1 inhibited A2-endo constitutive internalization and Nef-induced CD4 down-regulation, whereas it did not affect the activity of Nef on MHC-I. Moreover, trafficking of A2-endo was still affected by the viral protein, indicating additive effects of prototypic signals and Nef. Therefore, distinct trafficking pathways regulate clathrin-dependent and Nef-induced MHC-I modulation.

* Corresponding author. Mailing address: Unité Rétrovirus et Transfert Génétique, URA CNRS 1930, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 83 53. Fax: 33 1 45 68 89 40. E-mail: schwartz{at}pasteur.fr.

Journal of Virology, October 2000, p. 9256-9266, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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