HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.
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.


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-gamma 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.
van Wanrooij
Eva J A
EJ
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands. e.van.wanrooij@chem.leidenuniv.nl
Happé
Hester
H
Hauer
Arnaud D
AD
de Vos
Paula
P
Imanishi
Takeshi
T
Fujiwara
Hiromi
H
van Berkel
Theo J C
TJ
Kuiper
Johan
J
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005260:Female; D008024:Ligands; D018655:Lymphocyte Count; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000502:physiology
D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D018946:Chemokine CCL5; C515188:Cxcr3 protein, mouse; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D011973:Receptors, LDL; D002784:Cholesterol; C119369:TAK 779