title: Hemeoxygenase-1 as a Novel Driver in Ritonavir-Induced Insulin Resistance in HIV-1-Infected Patients.
abstract: Hemeoxygenase-1 (HO-1) has recently been identified as a major driver of metaflammation and obesity-related insulin resistance (IR). Drug-induced IR increases cardiovascular risk within the HIV-1-infected population receiving antiretroviral therapy (ART). We therefore investigated a possible role of HO-1 in ART-induced IR.
  
  
  
  Effects of HIV-1 protease inhibitor ritonavir and integrase inhibitor raltegravir (RAL) on expression levels of HO-1 and proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNFα), chemokine (C-C motif) ligand 5 (CCL5), and monocyte chemotactic protein 1 (MCP-1), were studied in monocyte and hepatocyte cell lines. Plasma levels of HO-1 and inflammatory markers were measured in insulin-resistant and insulin-sensitive HIV-1-infected patients under ART and seronegative controls.
  
  
  
  We show that, in contrast to RAL, ritonavir treatment significantly increases mRNA expression levels of HO-1, IL-8, TNFα, CCL5, and MCP-1 in vitro in a dose-dependent manner. HO-1 plasma levels were significantly higher in insulin-resistant compared to insulin-sensitive patients on ritonavir-boosted ART (lopinavir/ritonavir group: 3.90 ± 1.15 vs 2.56 ± 1.07 ng/mL, P < 0.005 and darunavir/ritonavir group: 3.16 ± 1.37 vs 2.28 ± 1.23 U/mL, P < 0.05) and were correlated with expression levels of TNFα in individuals on ritonavir-boosted ART (lopinavir/ritonavir group: r = 0.108, P < 0.05 and darunavir/ritonavir group: r = 0.221, P < 0.05) but not in HIV-1-infected individuals receiving RAL or in seronegative controls.
  
  
  
  HIV-1-infected patients on stable ART are often faced with non-AIDS-related metabolic comorbidities, increasing their individual cardiovascular risk. Here, we provide insight into a novel mechanism of ritonavir-induced IR involving proinflammatory properties of HO-1. Our initial observations might also provide prognostic value in the future to identify patients at risk for the development type 2 diabetes mellitus.
authors: *Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Laboratory of Immunological and Molecular Cancer Research, Paracelsus Medical University, Salzburg, Austria; †Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria; ‡Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria; §Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; ‖Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; and ¶Institute of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: Ninon
authors: N
authors: Taylor
authors: Iris
authors: I
authors: Kremser
authors: Simon
authors: S
authors: Auer
authors: Gregor
authors: G
authors: Hoermann
authors: Richard
authors: R
authors: Greil
authors: Elisabeth
authors: E
authors: Haschke-Becher
authors: Harald
authors: H
authors: Esterbauer
authors: Lukas
authors: L
authors: Kenner
authors: Hannes
authors: H
authors: Oberkofler
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D015497:HIV-1 / Q000302:isolation & purification; D051547:Heme Oxygenase-1 / Q000032:analysis*; D022781:Hepatocytes / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007333:Insulin Resistance; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D017320:HIV Protease Inhibitors; D051547:Heme Oxygenase-1; D019438:Ritonavir