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Journal of Virology, May 2009, p. 4574-4590, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.01800-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Suppression of Tetherin-Restricting Activity upon Human Immunodeficiency Virus Type 1 Particle Release Correlates with Localization of Vpu in the trans-Golgi Network{triangledown} ,{dagger}

Mathieu Dubé,1,2 Bibhuti Bhusan Roy,1 Pierre Guiot-Guillain,1,2 Johanne Mercier,1 Julie Binette,1,2 Grace Leung,1 and Éric A. Cohen1,2*

Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM),1 Department of Microbiology and Immunology, Université de Montréal, Montreal, Québec, Canada2

Received 27 August 2008/ Accepted 11 February 2009

Vpu promotes the efficient release of human immunodeficiency virus type 1 (HIV-1) by overcoming the activity of tetherin, a host cell restriction factor that retains assembled virions at the cell surface. In this study, we analyzed the intracellular localization and trafficking of subtype B Vpu in HIV-1-producing human cells. We found that mutations of conserved positively charged residues (R30 and K31) within the putative overlapping tyrosine- and dileucine-based sorting motifs of the Vpu hinge region affected both the accumulation of the protein in the trans-Golgi network (TGN) and its efficient delivery to late endosomal degradative compartments. A functional characterization of this mutant revealed that the mislocalization of Vpu from the TGN correlated with an attenuation of HIV-1 release. Interestingly, clathrin light chain small interfering RNA-directed disruption of Vpu trafficking from the TGN to the endosomal system slightly stimulated Vpu-mediated HIV-1 release and completely restored the activity of the Vpu R30A,K31A mutant. An analysis of the C-terminal deletion mutants of Vpu identified an additional determinant in the second helical structure of the protein, which regulated TGN retention/localization, and further revealed the functional importance of Vpu localization in the TGN. Finally, we show that a large fraction of Vpu colocalizes with tetherin in the TGN and provide evidence that the degree of Vpu colocalization with tetherin in the TGN is important for efficient HIV-1 release. Taken together, our results reveal that Vpu traffics between the TGN and the endosomal system and suggest that the proper distribution of Vpu in the TGN is critical to overcome the restricting activity of tetherin on HIV-1 release.

* Corresponding author. Mailing address: Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, 110 Avenue des Pins Ouest, Montreal, Quebec, Canada H2W 1R7. Phone: (514) 987-5804. Fax: (514) 987-5691. E-mail: eric.cohen{at}ircm.qc.ca

{triangledown} Published ahead of print on 25 February 2009.

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

Journal of Virology, May 2009, p. 4574-4590, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.01800-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bego, M. G., Dube, M., Mercier, J., Cohen, E. A. (2009). Effect of Calcium-Modulating Cyclophilin Ligand on Human Immunodeficiency Virus Type 1 Particle Release and Cell Surface Expression of Tetherin. J. Virol. 83: 13032-13036 [Abstract] [Full Text]  
  • Le Tortorec, A., Neil, S. J. D. (2009). Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein. J. Virol. 83: 11966-11978 [Abstract] [Full Text]  


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