title: Impact of CCR5, integrase and protease inhibitors on human endothelial cell function, stress, inflammation and senescence.
abstract: Ageing HIV-infected patients present an increased incidence of cardiovascular diseases, endothelial dysfunction being an early alteration. Some protease inhibitors (PIs) have been shown to increase the risk of cardiovascular disease. We evaluated here the effects of CCR5 or integrase inhibitors as compared to PIs on endothelial functions in vitro.
  
  
  
  Human coronary artery endothelial cells (HCAEC) from adult and old non-HIV-infected donors were treated for 15 days with the CCR5 inhibitor maraviroc, the integrase inhibitors dolutegravir or raltegravir or the ritonavir-boosted PIs, darunavir (DRV/r) or atazanavir (ATV/r), all at Cmaxconcentrations. We evaluated endothelial function, secretion of adhesion molecules and cytokines, inflammation, oxidative stress and senescence.
  
  
  
  In endothelial cells from adult donors, we confirmed that ATV/r and DRV/r adversely affected all assessed endothelial functions and enhanced senescence, these effects being mild for DRV/r. Raltegravir had no effect and maraviroc a mild anti-inflammatory effect. Dolutegravir decreased inflammation, by inhibiting the NFκB pathway, and senescence, by repressing the p21 pathway. Moreover, HCAEC from an old donor presented, constitutively, a high level of senescence. Raltegravir mildly affected inflammation and senescence while maraviroc and dolutegravir decreased oxidative stress, inflammation and senescence and improved endothelial dysfunction.
  
  
  
  We report here that the integrase inhibitor dolutegravir and the CCR5 inhibitor maraviroc reduced inflammation of human adult endothelial cells to different extents while raltegravir was neutral. Dolutegravir also reduced senescence, while PI/r increased inflammation and senescence. It is important to address the clinical relevance of these results.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Paris, France.|Inserm UMR_S938, Centre de Recherche Saint-Antoine, Paris, France.|ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Afonso
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Paris, France.|Inserm UMR_S938, Centre de Recherche Saint-Antoine, Paris, France.|ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Paris, France.|Inserm UMR_S938, Centre de Recherche Saint-Antoine, Paris, France.|ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Caron-Debarle
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Paris, France.|Inserm UMR_S938, Centre de Recherche Saint-Antoine, Paris, France.|ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D015815:Cell Adhesion Molecules; D016207:Cytokines; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species