Statins Inhibit HIV-1 Infection by Down-regulating Rho Activity

Abstract

Human immunodeficiency virus (HIV)-1 infectivity requires actin-dependent clustering of host lipid raft–associated receptors, a process that might be linked to Rho guanosine triphosphatase (GTPase) activation. Rho GTPase activity can be negatively regulated by statins, a family of drugs used to treat hypercholesterolemia in man. Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase. We show that statins decreased viral load and increased CD4+ cell counts in acute infection models and in chronically HIV-1–infected patients. Viral entry and exit was reduced in statin-treated cells, and inhibition was blocked by the addition of l-mevalonate or of geranylgeranylpyrophosphate, but not by cholesterol. Cell treatment with a geranylgeranyl transferase inhibitor, but not a farnesyl transferase inhibitor, specifically inhibited entry of HIV-1–pseudotyped viruses. Statins blocked Rho-A activation induced by HIV-1 binding to target cells, and expression of the dominant negative mutant RhoN19 inhibited HIV-1 envelope fusion with target cell membranes, reducing cell infection rates. We suggest that statins have direct anti–HIV-1 effects by targeting Rho.

Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors

“…Therefore, it is difficult to predict how inhibition of Rho prenylation in vivo will affect the activation state of Rho. The prevailing view is that statins inhibit Rho signaling by preventing Rho membrane association, and block agonist-induced Rho activation [12][13][14]30,35,36]. These studies generally examined short-term (< 6 h) effects of statins on acute, GEFmediated Rho activation.…”

“…However, in vitro studies suggest that the interaction of Rho with GAPs and GDIs may also be affected by Rho's prenylation state, and in vitro studies may not predict the effect of prenylation inhibitors on Rho activity in intact cells. There are conflicting reports in the literature, whether statins increase or decrease Rho·GTP levels in intact cells [12][13][14][15][16]. Therefore, we decided to study the effects of lovastatin on Rho signaling in human erythroleukemia (HEL) cells.…”

Whole genome expression profiling of hepatitis B virus-transfected cell line reveals the potential targets of anti-HBV drugs

“…1,[11][12][13][14] Inhibiting such cellular processes would be expected to have an antiviral effect. Evidence for this extends across many diverse virus types, including poxviruses, 15 herpesviruses, [16][17][18] retroviruses, 19 hepadnaviruses 20,21 and flaviviruses. 22 Moreover, any licensed drug that targets a human disease process affects the functioning of a cell or organ system in some way.…”

Farmacocinética das estatinas

“…Além disso, cresce o conceito de que praticamente todos os clássicos fatores de risco podem ter seu impacto na doença aterosclerótica atenuado pelo uso das estatinas, como tem sido mostrado em estudos de hipertensão arterial 28 ou diabetes 29 , além de situações mais recentes como indivíduos HIV em uso de antiretrovirais 30 ou em portadores de osteoporose 21,31 . Sendo assim, torna-se fundamental à boa prática clínica, a incorporação destes novos conceitos.…”