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

2004; Rockefeller University Press; Volume: 200; Issue: 4 Linguagem: Inglês

10.1084/jem.20040061

1540-9538

Gustavo del Real, Sonia Jiménez-Baranda, E. Mira, Rosa Ana Lacalle, Pilar Lucas, Concepción Gómez‐Moutón, Marta Alegret, José María Peña, Manuel Rodríguez Zapata, Melchor Álvarez‐Mon, Carlos Martínez‐A, Santos Mañes,

HIV/AIDS drug development and treatment

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.