Novel 2-Phenyl-1-Pyridin-2yl-Ethanone (PpY) Based Iron Chelators Increase Expression of IkBα and Heme Oxygenase-1 and Inhibit HIV-1

Abstract Abstract 1052 HIV-1 transcription is activated by HIV-1 Tat protein, which recruits CDK9/cyclin T1 and other host transcriptional co-activators to the HIV-1 promoter. Tat itself is phosphorylated by cell cycle kinase 2 (CDK2) and inhibition of CDK2 by small interfering RNA or iron chelators inhibits HIV-1 transcription. HIV-1 transcription is also activated by NF-kB that binds to HIV-1 LTR independent to Tat but can also be recruited Tat-dependently by CDK9/cyclin T1. Recently, induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1 in vitro and in vivo. Here, we analyzed the effect of novel phenyl-1-pyridin-2yl-ethanone (PPY) based iron chelators, PPYeT and PPYaT, on HIV-1. Both chelators efficiently inhibited one round of HIV-1 replication in T cells at low nanomolar IC50s without exhibiting cytotoxicity at 24 hrs incubation. The iron chelators efficiently bound intracellular labile iron as it was determined in calcein binding assays. Because we previously showed that iron chelators inhibited the activity of CDK9, we analyzed expression of several cellular genes dependent on CDK9. Unexpectedly, chelators were found to induce the expression of IkBα, an inhibitor of NF-kB (Fig1). Treatment with the iron chelators retained NF-kB in cytoplasm of the treated cells suggesting reduction in NF-kB in nucleus (Fig2). The chelators were also shown to induce HO-1 expression in cultured monocytes, likely to do a decrease of intracellular iron pool. This effect of iron chelators mimicked the effect of hemin treatment which also induced HO-1 and inhibited HIV-1 infection in our experimental conditions. Low nanomolar IC50s for the PPY-based iron chelators and lack of toxicity suggest their potential usefulness as future anti-retroviral therapeutics. Further studies are needed to investigate additional targets for iron chelators in HIV-1 life cycle that may include reverse transcription and capsid assembly. Therefore iron chelators need to be carefully assessed not only to understand the mechanism but also as a therapeutic strategy. Acknowledgments. This work was supported NIH Research Grants SC1GM082325, R25 HL003679, 2G12RR003048, 8G12MD007597, K25GM097501 and 1P30HL107253. Disclosures: No relevant conflicts of interest to declare.

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Heme and Iron Chelators Inhibit HIV-1 Through The Induction Of Heme Oxygenase 1, Ferroportin and IKBα

Blood ◽

10.1182/blood.v122.21.2198.2198 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2198-2198

Author(s):

Namita Kumari ◽

Sergei A Nekhai

Keyword(s):

Cell Cycle ◽

Protein Kinase C ◽

Protein Kinase ◽

Heme Oxygenase ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Iron Chelators ◽

Heme Oxygenase 1 ◽

Kinase C ◽

Hiv 1

Abstract Background Recently, HIV-1 infection was shown to be efficiently inhibited in macrophages and T-cells treated with hemin that was added extracellularly 1,2. Hemin administration to humanized transgenic mice significantly reduced HIV-1 viral load 1. Suppression of HIV-1 by hemin was mediated through the induction of (HO-1)1, via a protein kinase C-dependent pathway2. The inhibitory effect of hemin could be reversed by protoporphyrin, an HO-1 inhibitor 2. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1. We recently analyzed the role of HO-1 in protecting LPS-treated human macrophages against HIV-1 infection3. LPS-treated macrophages were negative for mature virions, expressed HO-1 and produced MIP1α, MIP1β and LD78β chemokines which led to a decreased CCR5 expression. Treatment with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) increased HIV-1 replication and decreased secretion of MIP1α, MIP1β, and LD78β chemokines. HO-1 also affects several proteins involved in cell cycle progression, and cell cycle is critical for HIV-1 progression. Hypoxia leads to induction and stabilization of HIF-1α and is inhibitory to HIV-1 replication. NF-kB is important for basal and Tat-activated HIV-1 transcription. Here we analyzed factors involved in HIV-1 transcription affected by HO-1 expression. Results HIV-1 replication was reduced in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication, suggesting that ferroportin plays a key role in the HIV-1 inhibition. Stable ferroportin knock down in THP1 cells led to the inability of hemin to inhibit HIV-1, again suggesting that ferroportin plays a key role in this process. In hemin-treated THP-1 cells, expression of p21, HIF-1α and IKBα mRNA was induced. The expression of IKBα, an inhibitor of NF-kB, reduced the level of p65 subunit of NF-kB. We obtained similar results in THP-1 cell treated with iron chelators, which also induced the expression of IKBα, HIF-1 and p21. THP-1 cells treated with hemin or iron chelators were arrested in G1 phase of cell cycle. Stable HIF-1a knockdown in promonocytic THP-1 cells increased HIV replication suggesting that HIF-1 might be a restriction factor for HIV-1. In contrast to iron chelators that inhibited enzymatic activity of CDK2 without affecting its protein level, hemin treatment reduced CDK2 expression at mRNA and protein levels. Conclusions Induction of HIF-1 regulatory pathway and iron export by ferroportin might protect hemin-treated THP-1 cells from HIV-1 infection. Additional molecular mechanisms of heme-mediated HIV-1 inhibition might also include NF-kB inhibition by IKBα and CDK2 inhibition leading to the inhibition of HIV-1 transcription. Our results point to novel therapeutics, such as the use of hemin and iron chelators, both of which are FDA approved for treatment for acute porphyries and iron overload. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. Literature 1. Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006;176(7):4252-4257. 2. Devadas K, Hewlett IK, Dhawan S. Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction. J Leukoc Biol. 2010;87(5):915-924. 3. Zhou ZH, Kumari N, Nekhai S, et al. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun. 2013;435(3):373-377. Disclosures: No relevant conflicts of interest to declare.

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Mir-217 Reverses the TKI Drug-Resistance of K562 Cells By the Downregulation of Heme Oxygenase-1

Blood ◽

10.1182/blood.v126.23.5138.5138 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5138-5138

Author(s):

Jishi Wang ◽

Chanjuan Wang ◽

Dan Ma ◽

Qin Fang ◽

Mei Ren

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Heme Oxygenase ◽

Kinase Inhibitors ◽

Conflicts Of Interest ◽

K562 Cells ◽

Heme Oxygenase 1 ◽

Tki Resistance

Abstract Upregulation of Heme oxygenase-1 (HO-1) strengthens drug-resistance to apoptotic death in the several kinds of cancer cells. Our recent study shows the higher levels of HO-1 expression in the thyrosine kinase inhibitors (TKI) resistance K562 cell line and cells from Imatinb-insensitive CML patients. The cause of HO-1 upregulating, though, is still unclear yet. MicroRNAs (miRNAs) play a significant role in the pathogenesis of cancer. They also are known as potential biomarkers and therapeutic targets. In the hematological neoplasm, miRNAs take part in not only cancer development, but also drug resistance. However, the problem has not been solved yet is how the microRNA involved in. This study found that the expression level of microRNAs were much different depended on if it is Imatinb-insensitive or not. The phenomenon was observed both in the K562 and CML patients. The mir217 was one of these microRNAs that significantly deceased when the K562 had been induced to resist the Imatinb. Meanwhile,TKI-resistance K562 cells can be in association with an increase in levels of HO-1 and a decrease in levels of miR-217. In the TKI-resistant K562 cells, the decreased of miR-217 upregulated the expression of HO-1 through a 3'-untranslated region(UTR) of HO-1 and induced the resistance against TKI. Interestingly, TKI-resistant K562 cells exposed to miR-217 mimic can partially make the cells be sensitized to TKI again in association with upregulation of miR-217 and downregulation of HO-1 in vitro. The IC50 of the TKI-resistant K562 cells exposed in 7.5uM Imatinb for 48 hours also decreased after transfecting miR-217 mimic for 48 hours. In our on-going experiment, the express level and interaction of HO-1 and miR-217 will be tested in K562 tumors growing in immune-deficient mice that were treated with the combination of mir-217 inhibitor, expression HO-1 virus and TKI. The express of HO-1 and miR-217 also will be examined in the TKI-insensitive CML patients and the mir217 and HO-1 regulated mechanism will be investigated in vivo. According to our results, the reversibility of the mir-217 downregulating Heme oxygenase-1 in the K562 cells with TKI drug tolerance likely provides a potentially exciting miRNA therapeutic strategy. MiRNAs therapy could be utilized as a powerful therapy which would focus to the drug-resistance patients. Drug-resistance cancer cells may be sensitized to former conventional or targeted chemotherapy. Disclosures No relevant conflicts of interest to declare.

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Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22041514 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1514 ◽

Cited By ~ 1

Author(s):

Akihiro Yachie

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Heme Oxygenase ◽

Inflammatory Diseases ◽

Cell Types ◽

Pharmacological Intervention ◽

Heme Oxygenase 1 ◽

Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

Clinical Science ◽

10.1042/cs20180675 ◽

2019 ◽

Vol 133 (1) ◽

pp. 117-134 ◽

Cited By ~ 7

Author(s):

Pamela L. Martín ◽

Paula Ceccatto ◽

María V. Razori ◽

Daniel E.A. Francés ◽

Sandra M.M. Arriaga ◽

...

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Bile Flow ◽

Driving Forces ◽

Membrane Lipids ◽

Ex Vivo ◽

Heme Oxygenase 1 ◽

Canalicular Transporters

Abstract We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.

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Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Blood ◽

10.1182/blood-2003-08-2781 ◽

2004 ◽

Vol 103 (9) ◽

pp. 3465-3473 ◽

Cited By ~ 63

Author(s):

Shane C. McAllister ◽

Scott G. Hansen ◽

Rebecca A. Ruhl ◽

Camilo M. Raggo ◽

Victor R. DeFilippis ◽

...

Keyword(s):

Endothelial Cells ◽

Heme Oxygenase ◽

Cell Biology ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Kaposi Sarcoma ◽

Heme Oxygenase 1 ◽

Spindle Cell Proliferation

Abstract Kaposi sarcoma (KS) is the most common AIDS-associated malignancy and is characterized by angiogenesis and the presence of spindle cells. Kaposi sarcoma-associated herpesvirus (KSHV) is consistently associated with all clinical forms of KS, and in vitro infection of dermal microvascular endothelial cells (DMVECs) with KSHV recapitulates many of the features of KS, including transformation, spindle cell proliferation, and angiogenesis. To study the molecular mechanisms of KSHV pathogenesis, we compared the protein expression profiles of KSHV-infected and uninfected DMVECs. This comparison revealed that heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in heme catabolism, was up-regulated in infected endothelial cells. Recent evidence suggests that the products of heme catabolism have important roles in endothelial cell biology, including apoptosis and angiogenesis. Here we show that HO-1 mRNA and protein are up-regulated in KSHV-infected cultures. Comparison of oral and cutaneous AIDS-KS tissues with normal tissues revealed that HO-1 mRNA and protein were also up-regulated in vivo. Increased HO-1 enzymatic activity in vitro enhanced proliferation of KSHV-infected DMVECs in the presence of free heme. Treatment with the HO-1 inhibitor chromium mesoporphyrin IX abolished heme-induced proliferation. These data suggest that HO-1 is a potential therapeutic target for KS that warrants further study. (Blood. 2004;103: 3465-3473)

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Alleviation of Cartilage Destruction by Sinapic Acid in Experimental Osteoarthritis

BioMed Research International ◽

10.1155/2019/5689613 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Dawei Cai ◽

Thomas W. Huff ◽

Jun Liu ◽

Tangbo Yuan ◽

Zijian Wei ◽

...

Keyword(s):

Heme Oxygenase ◽

Nuclear Translocation ◽

Sinapic Acid ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Transactivation Activity ◽

Nrf2 Signaling Pathway ◽

Primary Mouse

Sinapic acid (SA) modulates the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in chondrocytes. In order to test the hypothesis that SA is protective against the development of osteoarthritis (OA), primary mouse chondrocytes were treated in vitro with SA and the promoter transactivation activity of heme oxygenase 1 (HO-1), nuclear translocation of Nrf2, and protein expression of HO-1 were assayed. To test the hypothesis in vivo, a destabilization of the medial meniscus (DMM) model was used to induce OA in the knees of mice and SA was delivered orally to the experimental group. The chondrocytes were harvested for further analysis. The expression of HO-1 was similarly upregulated in cartilage from both the experimental mice and human chondrocytes from osteoarthritic knees. SA was found to enhance the promoter transactivation activity of heme oxygenase 1 (HO-1) and increase the expression of Nrf2 and HO-1 in primary chondrocytes. Histopathologic scores showed that the damage induced by the DMM model was significantly lower in the SA treatment group. The addition of a HO-1 inhibitor with SA did not show additional benefit over SA alone in terms of cartilage degradation or histopathologic scores. The expression of TNF-α, IL-1β, IL-6, MMP-1, MMP-3, MMP-13, ADAMTS4, and ADAMTS5 was significantly reduced both in vitro and in vivo by the presence of SA. Protein expressions of HO-1 and Nrf2 were substantially increased in knee cartilage of mice that received oral SA. Our results suggest that SA should be further explored as a preventative treatment for OA.

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Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1/2 and PI3K/Akt in EA.hy926 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7028478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Xiu E. Feng ◽

Tai Gang Liang ◽

Jie Gao ◽

De Peng Kong ◽

Rui Ge ◽

...

Keyword(s):

Heme Oxygenase ◽

Antioxidant Activities ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Key Enzyme ◽

Ea.Hy926 Cells ◽

Anti Inflammatory ◽

Mechanistic Basis

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-αproduction, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-αgeneration via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.

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Iron Chelation, Cell Cycle-Dependent Kinases and HIV-1 Transcription.

Blood ◽

10.1182/blood.v108.11.1550.1550 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1550-1550

Author(s):

Tatyana Ammosova ◽

Zufan Debebe ◽

Xiaomei Niu ◽

Des R. Richardson ◽

Marina Jerebtsova ◽

...

Keyword(s):

Cell Cycle ◽

T Cells ◽

Rna Polymerase Ii ◽

Iron Chelation ◽

Iron Chelators ◽

Intracellular Iron ◽

Cyclin T1 ◽

Protein Levels ◽

Cycle Dependent ◽

Hiv 1

Abstract Iron chelation leads to reduced cell cycle-dependent kinase 2 (CDK2) activity (reviewed in Biochim Biophys Acta2002;1603:31–46). Elongation of HIV-1 transcription is mediated by the interaction of HIV Tat with host cell cycle-dependent kinase 9 (CDK9)/cyclin T1, which phosphorylates the C-terminal domain of RNA polymerase II, and our recent studies indicate that CDK2 is also required for Tat-dependent transcription. We hypothesized that iron chelation may inhibit HIV transcription via reduced activity of cell cycle-dependent kinases. We utilized 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311; previously shown to inhibit CDK2 expression) and 4-[3,5-bis-(hydroxyphenyl) -1,2,4-triazol-1-yl]-benzoic acid (ICL670) to chelate intracellular iron. We analyzed the effect of these chelators on HIV-1 transcription using HeLa MAGI and CEM-GFP T-cells containing an integrated HIV-1 promoter and infected with adenovirus expressing HIV-1 Tat protein. Both chelators inhibited Tat-induced HIV-1 transcription, most profoundly in CEM-GFP T-cells. The chelators also inhibited one round of HIV-1 replication in CEM-T cells infected with pseudotyped HIV-1 virus. Treatment of HeLa MAGI and CEM-GFP T-cells with iron chelators decreased CDK9 protein levels and, to a lesser extent, CDK2 protein levels. Our findings provide evidence that iron chelators may inhibit HIV-1 transcription by altering expression of CDK9 and CDK2.

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Induction Of Ferroportin, Erg-1, p21 and IKBα In Sickle Cell Disease May Contribute To HIV-1 Inhibition

Blood ◽

10.1182/blood.v122.21.2250.2250 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2250-2250

Author(s):

Sergei A Nekhai ◽

Namita Kumari ◽

Denitra Breuer ◽

Charlee Mclean ◽

Tatiana Ammosova ◽

...

Keyword(s):

Sickle Cell Disease ◽

Enzymatic Activity ◽

Sickle Cell ◽

Iron Chelators ◽

Heme Oxygenase 1 ◽

Cell Disease ◽

Regulatory Pathways ◽

Cyclin T1 ◽

Cellular Iron ◽

Hiv 1

Abstract Background Hypoxia and low iron induce hypoxia-induced factor 1(HIF-1) by stabilizing its alpha subunit and deregulate HIV-1 which transcription and several other steps of life cycle depend on cellular iron [1]. HIV-1 transcription is inhibited at low oxygen levels and reduced cellular iron through deregulation of CDK9/cyclin T1 and CDK2/cyclin E. Sickle cell disease has low odds of ratio for HIV-1 infection [2]. Sickle cell disease (SCD) leads to hemolytic anemia which results in local ischemia and release of heme. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1 [1], although the mechanism of the inhibition was not clarified. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibits CDK2 and CDK9 activities and blocks HIV-1 transcription [1]. Because neither CDK2 nor CDK9 require iron for the enzymatic activity, we analyzed the expression of hypoxia and iron –dependent factors that may deregulate HIV-1 infection in SCD. Results Expression profiling followed by real-time PCR analysis showed induction of HO-1, p21, Erg-1, IKBα, HIF-1 and ferroportin mRNA and decrease of hepcidin mRNA in PBMCs from SCD patients. HIV-1 replication was reduced in SCD PBMCs comparing to normal controls, and also in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication in SCD PBMC and in hemin-treated THP-1 cells, suggesting that ferroportin played a key role in the HIV-1 inhibition in these settings. Stable ferroportin knock down in THP-1 cells led to the inability of hemin to inhibit HIV-1, suggesting that ferroportin played a key role in the heme-meidated HIV-1 inhibition. Stable HIF-1a knockdown in promonocytic THP1 cells increased HIV replication suggesting that HIF1α is a restriction factor for HIV-1. Iron chelators induced the expression of IKBα, an inhibitor of NF-kB and also induced the expression of HIF-1 and p21. Iron chelators also inhibited enzymatic activity of CDK2 and shifted CDK9/cyclin T1 from the large to the small complex making it unavailable for HIV-1 Tat recruitment. Hemin treatment induced expression of HO-1, ferroportin, IkBα, HIF1α and p21 thus mimicking the effect of iron chelators. Conclusions Hemolytic conditions of sickle cell disease upregulate hypoxia and iron regulatory pathways leading to refraction of HIV-1. Targeting cellular iron, ferroportin and HO-1 may lead to novel anti-HIV-1 therapeutics. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. References 1. Nekhai S, Kumari N, Dhawan S: Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 2013, 8(3):301-311. 2. Nouraie M, Nekhai S, Gordeuk VR: Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect 2012, 88(7):528-533. Disclosures: No relevant conflicts of interest to declare.

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