title: Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease.
abstract: The low incidence of HIV-1 infection in patients with sickle cell disease (SCD) and inhibition of HIV-1 replication in vitro under the conditions of low intracellular iron or heme treatment suggests a potential restriction of HIV-1 infection in SCD. We investigated HIV-1 ex vivo infection of SCD peripheral blood mononuclear cells (PBMCs) and found that HIV-1 replication was inhibited at the level of reverse transcription (RT) and transcription. We observed increased expression of heme and iron-regulated genes, previously shown to inhibit HIV-1, including ferroportin, IKBα, HO-1, p21, and SAM domain and HD domain-containing protein 1 (SAMHD1). HIV-1 inhibition was less pronounced in hepcidin-treated SCD PBMCs and more pronounced in the iron or iron chelators treated, suggesting a key role of iron metabolism. In SCD PBMCs, labile iron levels were reduced and protein levels of ferroportin, HIF-1α, IKBα, and HO-1 were increased. Hemin treatment induced ferroportin expression and inhibited HIV-1 in THP-1 cells, mimicking the HIV-1 inhibition in SCD PBMCs, especially as hepcidin similarly prevented HIV-1 inhibition. In THP-1 cells with knocked down ferroportin, IKBα, or HO-1 genes but not HIF-1α or p21, HIV-1 was not inhibited by hemin. Activity of SAMHD1-regulatory CDK2 was decreased, and SAMHD1 phosphorylation was reduced in SCD PBMCs and hemin-treated THP-1 cells, suggesting SAMHD1-mediated HIV-1 restriction in SCD. Our findings point to ferroportin as a trigger of HIV-1 restriction in SCD settings, linking reduced intracellular iron levels to the inhibition of CDK2 activity, reduction of SAMHD1 phosphorylation, increased IKBα expression, and inhibition of HIV-1 RT and transcription.
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Namita
authors.initials: N
authors.lastname: Kumari
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC; Department of Medicine, Howard University, Washington, DC.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ammosova
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Sharmin
authors.initials: S
authors.lastname: Diaz
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Xionghao
authors.initials: X
authors.lastname: Lin
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Niu
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Department of Microbiology, Howard University, Washington, DC.
authors.forename: Marina
authors.initials: M
authors.lastname: Jerebtsova
authors.affiliation: Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD.
authors.forename: Subhash
authors.initials: S
authors.lastname: Dhawan
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC; Department of Medicine, Howard University, Washington, DC.
authors.forename: Patricia
authors.initials: P
authors.lastname: Oneal
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC; Department of Medicine, Howard University, Washington, DC; Department of Microbiology, Howard University, Washington, DC.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai