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.
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain.
Gustavo
G
del Real
Sonia
S
Jiménez-Baranda
Emilia
E
Mira
Rosa Ana
RA
Lacalle
Pilar
P
Lucas
Concepción
C
Gómez-Moutón
Marta
M
Alegret
Jose María
JM
Peña
Manuel
M
Rodríguez-Zapata
Melchor
M
Alvarez-Mon
Carlos
C
Martínez-A
Santos
S
Mañes
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003599:Cytoskeleton / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008798:Mevalonic Acid; D051379:Mice; D016513:Mice, SCID; D011106:Polyisoprenyl Phosphates; D011233:Precipitin Tests; D012313:RNA / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012313:RNA; D002784:Cholesterol; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid