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Journal of Virology, July 2007, p. 7476-7490, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00308-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Productive Human Immunodeficiency Virus Type 1 Assembly Takes Place at the Plasma Membrane

Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal,¹ Department of Microbiology and Immunology, Université de Montréal, Montreal, Quebec, Canada²

Received 12 February 2007/ Accepted 3 May 2007

Gag proteins are necessary and sufficient to direct human immunodeficiency virus type 1 (HIV-1) particle assembly and budding. Recent evidence suggests that Gag targeting to late endosomal/multivesicular body (LE/MVB) compartments occurs prior to viral particle budding at the plasma membrane (PM). However, the route that Gag follows before reaching its steady-state destinations still remains a subject of debate. Using a subcellular fractionation method that separates PM from LE/MVB combined with pulse-chase labeling, we analyzed Gag trafficking in HIV-1-producing HEK 293T cells. Our results reveal that the majority of newly synthesized Gag is primarily targeted to the PM. While PM-targeted Gag was efficiently released, a significant fraction of the remaining cell surface-associated Gag was found to be subsequently internalized to LE/MVB, where it accumulated, thus accounting for the majority of LE/MVB-associated Gag. Importantly, this accumulation of Gag in LE/MVB was found to be cholesterol dependent since it was sensitive to the sterol-binding drugs filipin and methyl-ß-cyclodextrin. These results point towards the PM as being the primary site of productive HIV-1 assembly in cells that also support Gag accumulation in intracellular compartments.

Published ahead of print on 16 May 2007.

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