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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2642.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice

Eva J.A. van Wanrooij; Hester Happé; Arnaud D. Hauer; Paula de Vos; Takeshi Imanishi; Hiromi Fujiwara; Theo J.C. van Berkel; Johan Kuiper

From the Division of Biopharmaceutics (E.J.A.v.W., H.H., A.H., P.d.V., T.J.C.v.B., J.K.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands; and the Department of Bioorganic Chemistry (T.I.), Graduate School of Pharmaceutical Sciences, Osaka University, and the Department of Oncology (H.F.), Osaka University Graduate School of Medicine, Osaka, Japan.

Correspondence to Eva J.A. van Wanrooij, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail e.van.wanrooij{at}chem.leidenuniv.nl

Objective— HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques.

Methods and Results— TAK-779 treatment of low-density lipoprotein receptor^–deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN- area. TAK-779-treated animals showed a decreased percentage of CD4⁺ and CD8⁺ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals.

Conclusions— TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.

The HIV entry inhibitor TAK-779, a CCR5/CXCR3 antagonist, reduced atherogenesis by blocking the influx of Th1 cells into the plaque. We conclude that HIV entry inhibitors, because of their antiatherogenic properties, are preferred for treatment of HIV-positive patients.

Key Words: atherosclerosis • chemokines • HIV • T cells • CCR5

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Killing Two Birds With One Stone: Targeting Chemokine Receptors in Atherosclerosis and HIV Infection

Christian Weber
Arterioscler. Thromb. Vasc. Biol. 2005 25: 2448-2450. [Full Text] [PDF]

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