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Vol. 20, Issue 1, 498-508, January 1, 2009

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Human Discs Large Is a New Negative Regulator of Human Immunodeficiency Virus-1 Infectivity

Fabien Perugi^*, Delphine Muriaux^,, Bertha Cecilia Ramirez^*,, Sabah Chabani^*, Etienne Decroly, Jean-Luc Darlix, Vincent Blot^*,||, and Claudine Pique^*

*Department of Cell Biology, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale U567, 75014 Paris, France; LaboRetro, Institut National de la Santé et de la Recherche Médicale U758 Ecole Normale Supérieure de Lyon, 69364 Lyon, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6098, Luminy, 13288 Marseille, France

Submitted February 21, 2008; Revised October 3, 2008; Accepted October 15, 2008
Monitoring Editor: Keith E. Mostov

Human immunodeficiency virus (HIV)-1 replication is positively or negatively regulated through multiple interactions with host cell proteins. We report here that human Discs Large (Dlg1), a scaffold protein recruited beneath the plasma membrane and involved in the assembly of multiprotein complexes, restricts HIV-1 infectivity. The endogenous Dlg1 and HIV-1 Gag polyprotein spontaneously interact in HIV-1-chronically infected T cells. Depleting endogenous Dlg1 in either adherent cells or T cells does not affect Gag maturation, production, or release, but it enhances the infectivity of progeny viruses five- to sixfold. Conversely, overexpression of Dlg1 reduces virus infectivity by 80%. Higher virus infectivity upon Dlg1 depletion correlates with increased Env content in cells and virions, whereas the amount of virus-associated Gag or genomic RNA remains identical. Dlg1 knockdown is also associated with the redistribution and colocalization of Gag and Env toward CD63 and CD82 positive vesicle-like structures, including structures that seem to still be connected to the plasma membrane. This study identifies both a new negative regulator that targets the very late steps of the HIV-1 life cycle, and an assembly pathway that optimizes HIV-1 infectivity.

These authors contributed equally to this work.

Present address: ^|| Department of Exploratory Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10628 Science Center Dr., San Diego, CA 92121.

Address correspondence to: Claudine Pique (claudine.pique{at}inserm.fr)