title: HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.
abstract: 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.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands. e.van.wanrooij@chem.leidenuniv.nl
authors.forename: Eva J A
authors.initials: EJ
authors.lastname: van Wanrooij
authors.forename: Hester
authors.initials: H
authors.lastname: Happé
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Hauer
authors.forename: Paula
authors.initials: P
authors.lastname: de Vos
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imanishi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
mesh_terms: 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
chemical_list: 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