PMID- 27798431
OWN - NLM
STAT- MEDLINE
DCOM- 20170616
LR  - 20220129
IS  - 1944-7884 (Electronic)
IS  - 1525-4135 (Print)
IS  - 1525-4135 (Linking)
VI  - 75
IP  - 1
DP  - 2017 May 1
TI  - Hemeoxygenase-1 as a Novel Driver in Ritonavir-Induced Insulin Resistance in 
      HIV-1-Infected Patients.
PG  - e13-e20
LID - 10.1097/QAI.0000000000001223 [doi]
AB  - 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 1beta (IL-1beta), IL-6, IL-8, tumor 
      necrosis factor-alpha (TNFalpha), 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, TNFalpha, 
      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 TNFalpha 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.
FAU - Taylor, Ninon
AU  - Taylor N
AD  - *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; daggerDepartment of Laboratory Medicine, Paracelsus Medical 
      University, Salzburg, Austria; double daggerDepartment of Laboratory Medicine, Medical 
      University Vienna, Vienna, Austria;  section signLudwig Boltzmann Institute for Cancer 
      Research, Vienna, Austria;  ||Department of Clinical Pathology, Medical University 
      of Vienna, Vienna, Austria; and  paragraph signInstitute of Laboratory Animal Pathology, 
      University of Veterinary Medicine Vienna, Vienna, Austria.
FAU - Kremser, Iris
AU  - Kremser I
FAU - Auer, Simon
AU  - Auer S
FAU - Hoermann, Gregor
AU  - Hoermann G
FAU - Greil, Richard
AU  - Greil R
FAU - Haschke-Becher, Elisabeth
AU  - Haschke-Becher E
FAU - Esterbauer, Harald
AU  - Esterbauer H
FAU - Kenner, Lukas
AU  - Kenner L
FAU - Oberkofler, Hannes
AU  - Oberkofler H
LA  - eng
GR  - P 26011/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Acquir Immune Defic Syndr
JT  - Journal of acquired immune deficiency syndromes (1999)
JID - 100892005
RN  - 0 (Cytokines)
RN  - 0 (HIV Protease Inhibitors)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - Cell Line
MH  - Cytokines/analysis
MH  - Gene Expression Profiling
MH  - HIV Infections/*complications/*drug therapy/virology
MH  - HIV Protease Inhibitors/administration & dosage/*adverse effects
MH  - HIV-1/isolation & purification
MH  - Heme Oxygenase-1/*analysis
MH  - Hepatocytes/enzymology/immunology
MH  - Humans
MH  - *Insulin Resistance
MH  - Monocytes/enzymology/immunology
MH  - Ritonavir/administration & dosage/*adverse effects
PMC - PMC5298192
MID - EMS70284
COIS- The authors have no conflict of interest to disclose.
EDAT- 2016/11/01 06:00
MHDA- 2017/06/18 06:00
PMCR- 2017/08/01
CRDT- 2016/11/01 06:00
PHST- 2016/11/01 06:00 [pubmed]
PHST- 2017/06/18 06:00 [medline]
PHST- 2016/11/01 06:00 [entrez]
PHST- 2017/08/01 00:00 [pmc-release]
AID - 10.1097/QAI.0000000000001223 [doi]
PST - ppublish
SO  - J Acquir Immune Defic Syndr. 2017 May 1;75(1):e13-e20. doi: 
      10.1097/QAI.0000000000001223.