Session: 111. Hemoglobinopathies, excluding Thalassemia: Poster II
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.
Acknowledgements. This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253.
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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