Hepcidin induces HIV-1 transcription inhibited by ferroportin

Min Xu,Fatah Kashanchi,Willie Turner,Victor R Gordeuk,Jamie Rotimi,Altreisha Foster,Sergei Nekhai

doi:10.1186/1742-4690-7-104

Min Xu, Fatah Kashanchi + Show 5 more

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https://doi.org/10.1186/1742-4690-7-104

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Journal: Retrovirology	Publication Date: Dec 1, 2010
Citations: 89	License type: CC BY 2.0

Affiliation: Howard University, George Mason University

Abstract

BackgroundPhysiological regulation of cellular iron involves iron export by the membrane protein, ferroportin, the expression of which is induced by iron and negatively modulated by hepcidin. We previously showed that iron chelation is associated with decreased HIV-1 transcription. We hypothesized that increased iron export by ferroportin might be associated with decreased HIV-1 transcription, and degradation of ferroportin by hepcidin might in turn induce HIV-1 transcription and replication. Here, we analyzed the effect of ferroportin and hepcidin on HIV-1 transcription.ResultsExpression of ferroportin was associated with reduced HIV-1 transcription in 293T cells and addition of hepcidin to ferroportin-expressing cells counteracted this effect. Furthermore, exposure of promonocytic THP-1 cells to hepcidin was associated with decreased ferroportin expression, increased intracellular iron and induction of reporter luciferase gene expression. Finally, exposure of human primary macrophages and CD4+ T cells to hepcidin and iron was also associated with induction of viral production.ConclusionOur results suggest that the interplay between ferroportin-mediated iron export and hepcidin-mediated degradation of ferroportin might play a role in the regulation of HIV-1 transcription and may be important for understanding of HIV-1 pathogenesis.

Highlights

Physiological regulation of cellular iron involves iron export by the membrane protein, ferroportin, the expression of which is induced by iron and negatively modulated by hepcidin
These results suggest that HIV-1 transcription is negatively affected by the expression of ferroportin
Hepcidin had no effect on HIV-1 Luc expression when the cells were cotransfected with NIPP1-pA-RATA EGFP (Figure 4C). These results indicate that ferroportin inhibited HIV-1 gene expressing from the proviral genomic DNA and that the inhibition was reversed by exposure to hepcidin, which leads to degradation of ferroportin

Summary

Introduction

Physiological regulation of cellular iron involves iron export by the membrane protein, ferroportin, the expression of which is induced by iron and negatively modulated by hepcidin. We previously showed that iron chelation is associated with decreased HIV-1 transcription. We hypothesized that increased iron export by ferroportin might be associated with decreased HIV-1 transcription, and degradation of ferroportin by hepcidin might in turn induce HIV-1 transcription and replication. Cellular iron is important for HIV-1 transcription, as its removal by iron chelators is associated with inhibition of HIV-1 transcription in cultured cells [2,3]. Increased iron stores correlated with faster HIV-1 progression in HIV1- positive thalassemia major patients, in HIV-positive patients given oral iron and in HIV-positive subjects with the haptoglobin 2-2 polymorphism [4].

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