Statin-induced inhibition of HIV-1 release from latently infected U1 cells reveals a critical role for protein prenylation in HIV-1 replication.
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.
Amet
Tohti
T
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Nonaka
Mizuho
M
Dewan
Md Zahidunnabi
MZ
Saitoh
Yasunori
Y
Qi
Xiaohua
X
Ichinose
Shizuko
S
Yamamoto
Naoki
N
Yamaoka
Shoji
S
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D017368:Protein Prenylation; D034622:RNA Interference; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D019883:Alkyl and Aryl Transferases; D016655:HIV Core Protein p24; D011106:Polyisoprenyl Phosphates; D011498:Protein Precursors; D019821:Simvastatin; D014409:Tumor Necrosis Factor-alpha; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C514799:p24 protein, Human Immunodeficiency Virus Type 1; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; C083291:geranylgeranyltransferase type-I; C002963:geranylgeranyl pyrophosphate