Hemeoxygenase-1 as a Novel Driver in Ritonavir-Induced Insulin Resistance in HIV-1-Infected Patients

J Acquir Immune Defic Syndr. 2017 May 1;75(1):e13-e20. doi: 10.1097/QAI.0000000000001223.


Background: 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.

Methods: 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.

Results: 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.

Implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cytokines / analysis
  • Gene Expression Profiling
  • HIV Infections / complications*
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Protease Inhibitors / administration & dosage
  • HIV Protease Inhibitors / adverse effects*
  • HIV-1 / isolation & purification
  • Heme Oxygenase-1 / analysis*
  • Hepatocytes / enzymology
  • Hepatocytes / immunology
  • Humans
  • Insulin Resistance*
  • Monocytes / enzymology
  • Monocytes / immunology
  • Ritonavir / administration & dosage
  • Ritonavir / adverse effects*


  • Cytokines
  • HIV Protease Inhibitors
  • Heme Oxygenase-1
  • Ritonavir