geranylgeranyl-pyrophosphate and HIV-Infections

Latent infection of human immunodeficiency virus type 1 (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 geranylgeranylpyrophosphate, 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/gammac 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.

Topics: Alkyl and Aryl Transferases; Animals; Cell Line, Tumor; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Microscopy, Electron, Transmission; Polyisoprenyl Phosphates; Protein Precursors; Protein Prenylation; rab GTP-Binding Proteins; RNA Interference; Simvastatin; Tumor Necrosis Factor-alpha; Virus Replication