The Journal of Experimental Medicine
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Published 16 August 2004. doi:10.1084/jem.20040061
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 4, 541-547
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Brief Definitive Report

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

Gustavo del Real1, Sonia Jiménez-Baranda1, Emilia Mira1, Rosa Ana Lacalle1, Pilar Lucas1, Concepción Gómez-Moutón1, Marta Alegret2, Jose María Peña3, Manuel Rodríguez-Zapata4, Melchor Alvarez-Mon4, Carlos Martínez-A.1, and Santos Mañes1

1 Department of Immunology and Oncology, Centro Nacional de Biotecnología/Spanish Council for Scientific Research (CSIC), E-28049 Madrid, Spain
2 Department of Pharmacology and Therapeutical Chemistry, Facultad de Farmacia, Universidad de Barcelona, E-08028 Barcelona, Spain
3 Department de Medicina, Servicio de Medicina Interna, Hospital La Paz, E-28046 Madrid, Spain
4 Department of Diseases of the Immune System, School of Medicine, Hospital Principe de Asturias, Universidad de Alcalá de Henares, E-28801 Madrid, Spain

Address correspondence to Carlos Martínez-A., Dept. of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain. Phone: 34-91-585-4850; Fax: 34-91-372-0493; email: cmartineza{at}cnb.uam.es; or Santos Mañes, Dept. of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain. Phone: 34-91-585-4850; Fax: 34-91-372-0493; email: smanes{at}cnb.uam.es

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.

Key Words: cholesterol • actin cytoskeleton • small GTPases • lipid rafts • prenylation

G. del Real and S. Jiménez-Baranda contributed equally to this work.

G. del Real's present address is Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, E-28130 Madrid, Spain.


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