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Título : Statins Inhibit HIV-1 infection by down-regulating rho activity
Autor : Real, Gustavo del; Jiménez Baranda, Sonia; Mira, Emilia; Lacalle, Rosa Ana; Lucas, Pilar; Gómez-Moutón, Concepción; Alegret, Marta; Peña, José María; Rodríguez Zapata, Manuel; Álvarez-Mon, Melchor; Martínez-Alonso, Carlos; Mañes, Santos
Palabras clave : Cholesterol
Actin cytoskeleton
Small GTPases
Lipid rafts
Prenylation
Fecha de publicación : ago-2004
Editor: Rockefeller University Press
Citación : The Journal of Experimental Medicine, volume 200, number 4, august 16, 2004, pp. 541–547
Resumen: 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.
Descripción : Copyright © by The Rockefeller University Press
URI : http://hdl.handle.net/10261/3323
DOI: doi/10.1084/jem.20040061
ISSN: 0022-1007
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