Statins prevent HIV-1 infection in chronically infected individuals

Gustavo del Real,1 Sonia Jiménez-Baranda,1 Emilia Mira,1 Rosa Ana Lacalle,1 Pilar Lucas,1 Concepción Gómez-Moutón,1 Marta Alegret,2 Jose María Peña,3 Manuel Rodríguez-Zapata,4 Melchor Alvarez-Mon,4 Carlos Martínez-A.,1 and Santos Mañes1

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.

One area of HIV-1 research aims to understand the interplay between virus and host cell, to block key interactions between virus and host target, and to prevent virus propagation without the inconvenience of HAART. Effort has concentrated on the HIV-1 entry and budding processes, which require the formation of large clusters between viral and host cell proteins (1). Results suggest that HIV-1 entry into and exit from the host cell require actin cytoskeleton rearrangement and adequate cholesterol levels in host and viral membranes (2–13). A means remains to be found for specific targeting of these host factors to prevent HIV-1 propagation with minimal toxicity.

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used to treat hypercholesterolemia. HMG-CoA reductase produces mevalonic acid, a precursor for cholesterol biosynthesis and generation of isoprenoids that modify specific cell proteins posttranslationally. Rho guanosine triphosphatases (GTPases), which must be prenylated at their C terminus for function, are molecular switches that cycle between GTP-bound (active) and GDP-bound (inactive) states to control actin cytoskeleton remodeling in response to stimuli (14). By targeting HMG-CoA, statins block cholesterol biosynthesis, but also affect actin cytoskeleton rearrangement by inhibiting Rho GTPases (15).

We show that statins inhibited HIV-1 infection of SCID mice grafted with adult human PBMCs (SCID-hu-PBMC), an in vivo model of acute HIV-1 infection. Statins inhibited virus entry into and exit from target cells by targeting Rho geranylation. Strikingly, 1-mo oral statin administration reduced serum HIV-1 RNA copy number in chronically HIV-1–infected individuals not receiving HAART. Our results indicate that statins might be suitable antiretroviral drugs for more accessible AIDS treatment.

From: J Exp Med. 2004 August 16; 200(4): 541–547. doi: 10.1084/jem.20040061.