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Journal of Virology, July 2009, p. 6578-6590, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00548-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Nef Protein Targets CD4 to the Multivesicular Body Pathway{triangledown} ,{dagger}

Luis L. P. daSilva,{ddagger} Rachid Sougrat, Patricia V. Burgos, Katy Janvier,§ Rafael Mattera, and Juan S. Bonifacino*

Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Received 17 March 2009/ Accepted 20 April 2009

The Nef protein of human immunodeficiency virus type 1 downregulates the CD4 coreceptor from the surface of host cells by accelerating the rate of CD4 endocytosis through a clathrin/AP-2 pathway. Herein, we report that Nef has the additional function of targeting CD4 to the multivesicular body (MVB) pathway for eventual delivery to lysosomes. This targeting involves the endosomal sorting complex required for transport (ESCRT) machinery. Perturbation of this machinery does not prevent removal of CD4 from the cell surface but precludes its lysosomal degradation, indicating that accelerated endocytosis and targeting to the MVB pathway are separate functions of Nef. We also show that both CD4 and Nef are ubiquitinated on lysine residues, but this modification is dispensable for Nef-induced targeting of CD4 to the MVB pathway.

* Corresponding author. Mailing address: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-6368. Fax: (301) 402-0078. E-mail: juan{at}helix.nih.gov

{triangledown} Published ahead of print on 29 April 2009.

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

{ddagger} Present address: Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.

§ Present address: Institut Cochin, 22 rue Méchain, 75014 Paris, France.

Journal of Virology, July 2009, p. 6578-6590, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00548-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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