Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Kumari, Namita; Ammosova, Tatiana; Diaz, Sharmin; Lin, Xionghao; Niu, Xiaomei; Ivanov, Andrey; Jerebtsova, Marina; Dhawan, Subhash; O'Neal, Patricia; Nekhai, Sergeï

doi:10.1182/bloodadvances.2016000745

Cited by 28 publications

(54 citation statements)

References 66 publications

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“…The second strategy is to deplete cellular iron through regulating the gene expression involved in iron metabolism. HIV-1 reverse transcription and transcription was suppressed in PBMCs obtained from SCD patients due to increased expression of ferroportin and therefore lowered intracellular iron [14]. On the other hand, hepcidin agonists, such as minihepcidin and thiazolidinone derivatives, can reduce systemic iron levels by compromising the function of ferroportin [56].…”

Section: Antiviral Strategy Of Iron Chelationmentioning

confidence: 99%

“…HIV-1 transcription and replication were inhibited by number of iron chelators including 2-hydroxy-1naphthylaldehyde benzoyl hydrazine (311) and ICL670 (also known as deferasirox or exjade) [11], 2-benzoylpyridine 4allyl-3-thiosemicarbazone (Bp4aT) and 2-benzoylpyridine 4ethyl-3-thiosemicarbazone (Bp4eT) [12], and PPYeT and PPYaT [13]. In a recent study, ex vivo inhibition of HIV-1 in peripheral blood mononuclear cells (PBMCs) obtained from patients with sickle cell disease (SCD) was linked to the increased expression of ferroportin and reduced intracellular iron levels [14]. Thus, we can consider the potential of iron chelation as an alternative beneficial adjuvant in treating SARS-CoV-2 infection that we discuss below.…”

Section: Introductionmentioning

confidence: 99%

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Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

Liu

Zhang

Nekhai

et al. 2020

Curr Clin Micro Rpt

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137

170

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Purpose of the review The ongoing outbreak of novel coronavirus pneumonia caused by the 2019 novel coronavirus (SARS-CoV-2) in China is lifting widespread concerns. Thus, therapeutic options are urgently needed, and will be discussed in this review. Recent findings Iron-containing enzymes are required for viruses most likely including coronaviruses (CoVs) to complete their replication process. Moreover, poor prognosis occurred in the conditions of iron overload for patients upon infections of viruses. Thus, limiting iron represents a promising adjuvant strategy in treating viral infection through oral uptake or venous injection of iron chelators, or through the manipulation of the key iron regulators. For example, treatment with iron chelator deferiprone has been shown to prolong the survival of acquired immunodeficiency syndrome (AIDS) patients. Increasing intracellular iron efflux via increasing iron exporter ferroportin expression also exhibits antiviral effect on human immunodeficiency virus (HIV). The implications of other metals besides iron are also briefly discussed. Summary For even though we know little about iron regulation in COVID-19 patients thus far, it could be deduced from other viral infections that iron chelation might be an alternative beneficial adjuvant in treating COVID-19.

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Section: Antiviral Strategy Of Iron Chelationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

Liu

Zhang

Nekhai

et al. 2020

Curr Clin Micro Rpt

Self Cite

137

170

View full text Add to dashboard Cite

show abstract

“…In addition to regulation of SAMHD1 expression on transcriptional and protein levels, SAMHD1 can be posttranslationally modified by phosphorylation. Threonine residue 592 has been postulated to be phosphorylated by the cyclin-dependent kinases CDK1 and CDK2 requiring upstream activity of CDK6 [22,23], and cyclins A2, B1, D2, D3, and L2 have been implicated in this process [23][24][25][26][27][28][29][30][31][32][33][34]. Even though tetramer stability might be influenced by T592 phosphorylation [35], hydrolase activity is not [34,[36][37][38].…”

Section: Cell Cycle Regulation Of Samhd1mentioning

confidence: 99%

With me or against me: Tumor suppressor and drug resistance activities of SAMHD1

Herold

Rudd

Sanjiv

et al. 2017

Experimental Hematology

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Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses. Increasing evidence supports the role of SAMHD1 as a tumor suppressor. However, SAMHD1 also can act as a resistance factor to nucleoside-based chemotherapies by hydrolyzing their active triphosphate metabolites, thereby reducing response of various malignancies to these anticancer drugs. Hence, informed cancer therapies must take into account the ambiguous properties of SAMHD1 as both an inhibitor of uncontrolled proliferation and a resistance factor limiting the efficacy of anticancer treatments. Here, we provide evidence that SAMHD1 is a double-edged sword for patients with acute myelogenous leukemia (AML). Our time-dependent analyses of The Cancer Genome Atlas (TCGA) AML cohort indicate that high expression of SAMHD1, even though it critically limits the efficacy of high-dose ara-C therapy, might be associated with more favorable disease progression.

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“…1), induced HIV-1 replication [86] suggesting that ferroportin restricted HIV-1 expression. We recently investigated the mechanism of reduced HIV-1 ex vivo infection in PBMC obtained from patients with sickle cell disease [87]. We observed the expression of ferroportin, reduction of intracellular iron, decreased CDK2 activity and reduced SAMHD1 phosphorylation (Fig.…”

Section: Inhibition Of Hiv-1 Transcription With Iron Chelatorsmentioning

confidence: 99%

“…4), and increased expression IKBα (Fig. 1), cumulatively leading to the inhibition of HIV-1 transcription and reverse transcription [87]. Cellular iron levels can also be increased by Nef, an HIV-1 accessory protein, that down regulates the expression of human hemochromatosis protein (HFE).…”

Section: Inhibition Of Hiv-1 Transcription With Iron Chelatorsmentioning

confidence: 99%

Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

Lin¹,

Ammosova²,

Kumari³

et al. 2017

CPD

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Background Despite efficient suppression of HIV-1 replication, current antiviral drugs are not able to eradicate HIV-1 infection. Permanent HIV-1 suppression or complete eradication requires novel biological approaches and therapeutic strategies. Our previous studies showed that HIV-1 transcription is regulated by host cell protein phosphatase-1. We also showed that HIV-1 transcription is sensitive to the reduction of intracellular iron that affects cell cycle-dependent kinase 2. We developed protein phosphatase 1-targeting small molecules that inhibited HIV-1 transcription. We also found an additional class of protein phosphatase-1-targeting molecules that activated HIV-1 transcription and reported HIV-1 inhibitory iron chelators and novel curcumin analogs that inhibit HIV-1. Here, we review HIV-1 transcription and replication with focus on its regulation by protein phosphatase 1 and cell cycle dependent kinase 2 and describe novel small molecules that can serve as future leads for anti-HIV drug development. Results Our review describes in a non-exhaustive manner studies in which HIV-1 transcription and replication are targeted with small molecules. Previously, published studies show that HIV-1 can be inhibited with protein phosphatase-1-targeting and iron chelating compounds and curcumin analogs. These results are significant in light of the current efforts to eradicate HIV-1 through permanent inhibition. Also, HIV-1 activating compounds can be useful for “kick and kill” therapy in which the virus is reactivated prior to its inhibition by the combination antiretroviral therapy. Conclusion The studies described in our review point to protein phosphatase-1 as a new drug target, intracellular iron as subject for iron chelation and novel curcumin analogs that can be developed for novel HIV-1 transcription-targeting therapeutics.

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Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Cited by 28 publications

References 66 publications

Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

With me or against me: Tumor suppressor and drug resistance activities of SAMHD1

Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

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