on October 20, 2005
Published online before print October 20, 2005, doi: 10.1161/01.ATV.0000192018.90021.c0
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Submitted on April 12, 2005
Accepted on September 28, 2005
HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice
Eva J.A. van Wanrooij *;
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.
* To whom correspondence should be addressed. 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.
Key words: atherosclerosis • chemokines • HIV • T cells • CCR5
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