HIV-1 infection in sickle cell disease and sickle cell trait: role of iron and innate response

Abstract

Introduction: Sickle cell disease (SCD), an inherited hemoglobinopathy, affects primarily African Americans in the U.S.A. In addition, about 15% African Americans carry sickle cell trait (SCT). Despite the risk associated with blood transfusions, SCD patients have lower risk of acquiring HIV-1 infection. SCT individuals might also have some protection from HIV-1 infection.

Areas covered: Here, we will review recent and previous studies with the focus on molecular mechanisms that might underlie and contribute to the protection of individuals with SCD and SCT from HIV-1 infection. As both of these conditions predispose to hemolysis, we will focus our discussion on the effects of systemic and intracellular iron on HIV-1 infection and progression. We will also review changes in iron metabolism and activation of innate antiviral responses in SCD and SCT and their effects on HIV-1 infection.

Expert opinion: Previous studies, including ours, showed that SCD might protect from HIV-1 infection. This protection is likely due to the upregulation of complex protein network in response to hemolysis, hypoxia and interferon signaling. These findings are important not only for HIV-1 field but also for SCD cure efforts as antiviral state of SCD patients may adversely affect lentivirus-based gene therapy efforts.

Keywords: HIV-1 infection; Sickle cell disease; anti-viral innate immune response; iron metabolism; sickle cell trait.

Fig. 1.. Schematic representation of the effect of iron and anti-viral restriction factors on HIV-1 replication.

HIV-1 replication cycle steps (black arrows) include viral fusion and entry, reverse transcription, integration of the proviral DNA, transcription and export of viral RNA, translation, and viral assembly. Involvement of intracellular iron is indicated by black dotted arrows. HIV-1 reverse transcription regulation by SAMHD1 and RNR2, and upstream regulation of SAMHD1 by CDK2/cyclin E are shown. HIV-1 transcription activation by HIV-1 Tat protein that binds to HIV-1 TAR RNA and recruits host cell CDK9/cyclin T1 is shown. Also shown is the activation of CDK9/cyclin T1 by CDK2/cyclin E and induction of basal HIV-1 transcription by NF-κB. The inhibitory effect of iron chelators on CDK2/cyclin E, NF-kB, RNA export and HIV-1 translation and assembly are shown. Ferritin bound Fe³⁺ by transferrin receptor (TFR) and negative effect of HIV-1 Nef protein on HFE leading to the upregulation of TFR are shown. Hepcidin is shown to indicate its negative effect on FPN.

Fig. 2.. Schematic representation of the SCD effect on HIV-1 replication at molecular level.

SCD conditions increase expression of host genes including NFKBIA (IκBα), HIF1A (HIF-1α), CDKNA1 (p21), HMOX1 (HO-1) and SLC40A1 (FPN). Expression of FPN leads to the reduction of intracellular iron. The lower iron levels stabilize transferring receptor (TFR) mRNA and HIF-1α and induce IκBα and p21 expression. Also, lower iron levels inhibit enzymatic activity of CDK2/cyclin E, reduces SAMHD1 phosphorylation and induces HIV reverse transcription inhibition by SAMHD1.

Fig. 3.. Schematic representation of the sickle cell trait (SCT) effect on HIV-1 replication at molecular level.

In SCT condition, increased expression of HMOX-1 and SAMHD1 was observed. Protein levels of RNR2 were downregulated.