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

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 1&bgr; (IL-1&bgr;), IL-6, IL-8, tumor necrosis factor-&agr; (TNF&agr;), 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, TNF&agr;, 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 TNF&agr; in individuals on ritonavir-boosted ART (lopinavir/ritonavir group: r2 = 0.108, P < 0.05 and darunavir/ritonavir group: r2 = 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.