Sickle-cell disease (SCD) is a hereditary disorder that affects approximately 100,000 people in the USA, primarily of African descent. Single E6V mutation in b-globin gene leads to the production of hemoglobin S (HbS) and development of chronic hemolytic anemia. Our recent analysis of a national hospital discharge survey showed an association of SCD with lower frequency of HIV-1 diagnosis (odds ratio 0.33) suggesting that SCD might offer a protection from HIV-1. We hypothesize that hemolytic anemia in SCD leads to inhibition of HIV-1 transcription through the activation of heme-, iron and oxygen-dependent pathways. Heme induces transcription of iron regulatory genes in macrophages, including heme oxygenase-1 (HO-1), ferritin and iron export protein, ferroportin leading to the increased iron export and reduction of cellular iron. In SCD, expression of HO-1 is increased whereas expression of hepcidin that regulates internalization and degradation of ferroportin is decreased (and also our preliminary data). Induction of HO-1 by heme inhibits HIV-1 infection in macrophages and T-cells in vitro and in HIV-1 infected humanized mice. We have previously shown that HIV-1 transcription is inhibited by iron chelators or ferroportin. Iron chelators inhibi cellular activities of CDK2 and CDK9, both critical for HIV-1 transcription. Our recent findings demonstrate that CDK2 directly phosphorylates CDK9's Ser90 resulting in the activation of HIV-1 transcription. We, therefore, hypothesize that increased blood heme concentration, ischemia and decreased hepcidin will elevate levels and activity of HO-1 and ferroportin, reduce cellular iron and upregulate HIF-1 pathway leading to the induction of Egr-1, p21 and inhibition of CDK2 and CDK9. Upregulation of this protein network will lead to the inhibition HIV-1 transcription and viral replication in SCD condition.
In Specific Aim 1, we will analyze HIV-1 inhibition in SCD and SCD trait.
In Specific Aim 2, we will analyze molecular mechanisms of HIV-1 inhibition in SCD and SCD trait.
In Specific Aim 3, we will analyze novel inhibitors HO-1, ferroportin and hepcidin pathways in vivo. Collectively, our proposed research is designed to elucidate the molecular mechanisms of HIV-1 inhibition in the settings of SCD and SCD trait. Our studies will uncover novel mechanisms of HIV-1 regulation by heme, ferroportin, hepcidin, and iron. Our proposed studies are significant because they may lead to novel therapeutics, such as the use of hemin and iron chelators.

Public Health Relevance

Sickle Cell Disease is a hereditary disorder which protects against malaria and may have a protective effect against HIV-1 infection. This is an example of selective human mutation that is restrictive to HIV-1. The proposed research is relevant to public health because it is aimed at understanding the mechanism of protection against HIV-1 in the setting of Sickle Cell Disease. Uncovering the mechanism of HIV-1 resistance is likely to generate novel therapeutic approaches, and thus the proposed research is relevant to the NIH mission that pertains to a reduced vulnerability of the population to viral infections that include infection with HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125005-03
Application #
9010978
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Zou, Shimian
Project Start
2014-05-05
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Howard University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Khaibullina, Alfia; Adjei, Elena A; Afangbedji, Nowah et al. (2018) RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice. Haematologica 103:787-798
Ivanov, Andrey; Lin, Xionghao; Ammosova, Tatiana et al. (2018) HIV-1 Tat phosphorylation on Ser-16 residue modulates HIV-1 transcription. Retrovirology 15:39
Jerebtsova, Marina; Saraf, Santosh L; Soni, Simran et al. (2018) Urinary orosomucoid is associated with progressive chronic kidney disease stage in patients with sickle cell anemia. Am J Hematol 93:E107-E109
Jerebtsova, Marina; Saraf, Santosh L; Lin, Xionghao et al. (2018) Identification of ceruloplasmin as a biomarker of chronic kidney disease in urine of sickle cell disease patients by proteomic analysis. Am J Hematol 93:E45-E47
Lin, Xionghao; Ammosova, Tatyana; Kumari, Namita et al. (2017) Protein Phosphatase-1 -targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals. Curr Pharm Des 23:4122-4132
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Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A et al. (2016) Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment. Infect Dis (Auckl) 9:21-32
Huang, Hanxia; Konduru, Krishnamurthy; Solovena, Veronica et al. (2016) Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection. Curr Trends Immunol 17:117-123
Ammosova, Tatiana; Washington, Kareem; Rotimi, Jamie et al. (2016) Protein Phosphatase-1 Regulates Expression of Neuregulin-1. Biology (Basel) 5:
Kumari, Namita; Ammosova, Tatiana; Diaz, Sharmin et al. (2016) Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease. Blood Adv 1:170-183

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