Journal
MICROBES AND INFECTION
Volume 10, Issue 5, Pages 471-480Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.micinf.2008.01.009
Keywords
statins; prenylation; HIV-1; Rab11a; small GTPases
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Latent infection of human immunodeficiency virus type I (HIV-1) represents a major hurdle in the treatment of acquired immunodeficiency syndrome (AIDS) patients. Statins were recently reported to suppress acute HIV-1 infection and reduce infectious virion production, but the precise mechanism of inhibition has remained elusive. Here we demonstrate that lypophilic statins suppress HIV-1 virion release from tumor necrosis factor alpha-stimulated latently infected U1 cells through inhibition of protein geranylgeranylation, but not by cholesterol depletion. Indeed, this suppression was reversed by the addition of geranyl geranylpyrophosphate, and a geranylgeranyltransferase-1 inhibitor reduced HIV-1 production. Notably, silencing of the endogenous Rab11a GTPase expression in U1 cells by RNA interference destabilized Gag and reduced virion production both in vitro and in NOD/SCID/gamma c(null) mice. Our findings thus suggest that small GTPase proteins play an important role in HIV-1 replication, and therefore could be attractive molecular targets for anti-HIV-1 therapy. (C) 2008 Elsevier Masson SAS. All rights reserved.
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