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Sickle cell disease (SCD) is a characterized by hemolysis, vaso-occlusion and ischemia. Several previous studies pointed to a possibility that SCD patients might be protected from HIV-1 infection. These studies described low prevalence of anti-HIV-1 antibodies in SCD patients transfused with potentially HIV-1 infected blood;1 higher number of long-term non-progressors among HIV-1 infected SCD patients, 2 and a lower frequency of HIV diagnosis among SCD patients (odds ratio 0.33).3 This study aims to decipher a mechanism of HIV-1 restriction in PBMC from SCD patient infected with HIV-1 ex vivo. HIV-1 replication in SCD PBMC was inhibited at the level of reverse transcription and transcription implicating the involvement of post-entry and transcription restriction factors. SAM domain and HD domain-containing protein 1 (SAMHD1) restricts HIV-1 infection in in myeloid cells. 4,5 by reducing intracellular nucleotide pool and blocking reverse transcription. SAMHD1 phosphorylation on Thr-592 by CDK2 or CDK1 inactivates it and prevents HIV-1 inhibition. We showed that SAMHD1 phosphorylation was reduced in SCD PBMCs and in hemin-treated promonocytic THP-1 cells. Moreover, knock-down of SAMHD1 prevent hemin-mediated inhibition of HIV-1 in THP-1 cells. We also detected a reduction of CDK2 activity in SCD PBMCs and in hemin-treated THP-1 cells which can explain reduced SAMHD1 phosphorylation. Previously, we showed that CDK2 activity is inhibited when intracellular iron levels are depleted by iron chelators. We observed reduced intracellular labile iron levels and increased expression of iron export protein, ferroportin and HIF-1α in SCD PBMCs. Importantly, treatment of SCD PBMCs with hepcidin alleviated HIV-1 inhibition. Unaltered hepcidin levels in plasma of SCD patients suggest that ferroportin expression is sustained in SCD PBMC. Our study points out to ferroportin as upstream regulator of SAMHD1 and links a reduction in iron levels, inhibition of CDK2 activity and a decrease in SAMHD1 phosphorylation to the inhibition of HIV-1 infection in SCD. Acknowledgments. This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. Literature 1. Castro O, Saxinger C, Barnes S, Alexander S, Flagg R, Frederick W. Prevalence of antibodies to human immunodeficiency virus and to human T cell leukemia virus type I in transfused sickle cell disease patients. J Infect Dis. 1990;162(3):743-745. 2. Bagasra O, Steiner RM, Ballas SK, et al. Viral burden and disease progression in HIV-1-infected patients with sickle cell anemia. Am J Hematol. 1998;59(3):199-207. 3. Nouraie M, Nekhai S, Gordeuk VR. Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in US hospital discharge records: a cross-sectional study. Sex Transm Infect. 2012. 4. Hrecka K, Hao C, Gierszewska M, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 2011;474(7353):658-661. 5. Laguette N, Sobhian B, Casartelli N, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011;474(7353):654-657. Disclosures No relevant conflicts of interest to declare.