CCR5 as a treatment target in pulmonary arterial hypertension

Circulation. 2014 Sep 9;130(11):880-891. doi: 10.1161/CIRCULATIONAHA.114.010757. Epub 2014 Jul 3.


Background: Pulmonary arterial hypertension (PH), whether idiopathic or related to underlying diseases such as HIV infection, results from complex vessel remodeling involving both pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation. CCR5, a coreceptor for cellular HIV-1 entry expressed on macrophages and vascular cells, may be involved in the pathogenesis of PH. Maraviroc is a new CCR5 antagonist designed to block HIV entry.

Methods and results: Marked CCR5 expression was found in lungs from patients with idiopathic PH, in mice with hypoxia-induced PH, and in Simian immunodeficiency virus-infected macaques, in which it was localized chiefly in the PA-SMCs. To assess the role for CCR5 in experimental PH, we used both gene disruption and pharmacological CCR5 inactivation in mice. Because maraviroc does not bind to murine CCR5, we used human-CCR5ki mice for pharmacological and immunohistochemical studies. Compared with wild-type mice, CCR5-/- mice or human-CCR5ki mice treated with maraviroc exhibited decreased PA-SMC proliferation and recruitment of perivascular and alveolar macrophages during hypoxia exposure. CCR5-/- mice reconstituted with wild-type bone marrow cells and wild-type mice reconstituted with CCR5-/- bone marrow cells were protected against PH, suggesting CCR5-mediated effects on PA-SMCs and macrophage involvement. The CCR5 ligands CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of human and human-CCR5ki mouse PA-SMCs; maraviroc inhibited both effects. Maraviroc also reduced the growth-promoting effects of conditioned media from CCL5-activated macrophages derived from human-CCR5ki mice on PA-SMCs from wild-type mice.

Conclusion: The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.

Keywords: hypertension, pulmonary; inflammation; receptors, CCR5; vascular smooth muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCR5 Receptor Antagonists*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclohexanes / pharmacology*
  • Disease Models, Animal
  • Familial Primary Pulmonary Hypertension
  • HIV Fusion Inhibitors / pharmacology
  • HIV Infections / drug therapy
  • HIV Infections / pathology
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / virology
  • Hypoxia / drug therapy
  • Hypoxia / pathology
  • Macaca mulatta
  • Macrophages / drug effects
  • Male
  • Maraviroc
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / pathology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology
  • Receptors, CCR5 / genetics
  • Simian Acquired Immunodeficiency Syndrome / drug therapy*
  • Simian Acquired Immunodeficiency Syndrome / pathology
  • Triazoles / pharmacology*


  • CCR5 Receptor Antagonists
  • CCR5 protein, human
  • CCR5 protein, mouse
  • Cyclohexanes
  • HIV Fusion Inhibitors
  • Receptors, CCR5
  • Triazoles
  • Maraviroc