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Journal of Virology, June 2003, p. 6931-6945, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6931-6945.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeting of the Human Immunodeficiency Virus Type 1 Envelope to the trans-Golgi Network through Binding to TIP47 Is Required for Env Incorporation into Virions and Infectivity

Department of Infectious Diseases, Institut Cochin, INSERM U567, CNRS UMR 8104, Université R. Descartes Paris V, 75014 Paris,¹ Institut J. Monod, 75251 Paris cedex 05, France²

Received 14 November 2002/ Accepted 3 March 2003

Here, we report that human immunodeficiency virus type 1 (HIV-1) Env glycoprotein is located mainly in the trans-Golgi network (TGN) due to determinants present in the cytoplasmic domain of the transmembrane gp41 glycoprotein (TMgp41). Internalization assays demonstrated that Env present at the cell surface returns to the TGN. We found that the cytoplasmic domain of TMgp41 binds to TIP47, a protein required for the transport of mannose-6-phosphate receptors from endosomes to the TGN. Overexpression of a mutant of TIP47 affected the transport of Env from endosomes to the TGN. Retrograde transport of Env to the TGN requires a Y₈₀₂W₈₀₃ diaromatic motif present in the TMgp41 cytoplasmic domain. Mutation of this motif abolished both targeting to the TGN as well as interaction with TIP47. These data support the view that binding of TIP47 to HIV-1 Env facilitates its delivery to the TGN. Lastly, we show that virus mutated in the Y₈₀₂W₈₀₃ motif is poorly infectious and presents a defect in Env incorporation, supporting a model in which retrograde transport of Env is implicated in the optimization of fully infectious HIV-1 production.

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