geranylgeranyl-pyrophosphate and Acquired-Immunodeficiency-Syndrome

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.

Topics: Acquired Immunodeficiency Syndrome; Animals; CD4 Lymphocyte Count; Cells, Cultured; Cholesterol; Cytoskeleton; Disease Models, Animal; Down-Regulation; Electrophoresis, Polyacrylamide Gel; HIV-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukocytes, Mononuclear; Mevalonic Acid; Mice; Mice, SCID; Polyisoprenyl Phosphates; Precipitin Tests; rho GTP-Binding Proteins; RNA