Statins inhibit HIV-1 infection by down-regulating Rho activity

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.

Bibliographic Details

Main Authors:	del Real, G., Jiménez-Baranda, S., Mira, E., Lacalle, R. A., Lucas, P., Gómez-Moutón, C., Alegret, M., Peña, J. M., Rodríguez-Zapata, M., Alvarez-Mon, M., Martínez-A, C., Mañes, S.
Format:	journal article biblioteca
Language:	eng
Published:	2004
Online Access:	http://hdl.handle.net/20.500.12792/1015
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