Abstract
Background Intracellular iron and oxygen levels regulate HIV-1 replication by affecting several steps in the HIV-1 life cycle including transcription [1]. Low oxygen levels and reduced cellular iron are inhibitory as CDK9/cyclin T1 and CDK2/ cyclin E activities are reduced and HIV-1 transcription is inhibited. The alpha subunit of hypoxia-induced factor 1 (HIF1a) is stabilized under hypoxia and in the conditions of low cellular iron. 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]. As neither CDK2 nor CDK9 requires iron for their enzymatic activity, an apparent upstream regulation is involved. Also, 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. Here we analyzed the effect of iron chelators on HIV-1 transcription and replication and also analyzed the effect of heme, a condition present in sickle cell disease that may protect against HIV-1 infection [2].
Highlights
Intracellular iron and oxygen levels regulate HIV-1 replication by affecting several steps in the HIV-1 life cycle including transcription [1]
The chelators induce the expression of HIF1a, increased the expression of p21, inhibited enzymatic activity of CDK2 and shifted CDK9 from the large to the small complex
HIF1a knockdown in promonocytic THP1 cells led to increased HIV-1 replication suggesting that HIF1a may restrict HIV-1
Summary
Intracellular iron and oxygen levels regulate HIV-1 replication by affecting several steps in the HIV-1 life cycle including transcription [1]. Results Novel iron chelators, PpY-eT and PpY-aT, efficiently inhibited HIV-1 and induced the expression of IkBa, an inhibitor of NF-kB, that was not previously reported.
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