Upregulation of Antiviral Factors That Inhibit HIV-1 Infection in Sickle Cell Disease

BACKGROUND: Sickle cell disease (SCD) is a hereditary disorder characterized by hemolysis and changes in iron metabolism. We previously showed that increased expression of ferroportin (FPN), an iron export protein, leads to reduced intracellular iron and activation of antiviral response in SCD PBMCs. Here, we recruited a cohort of SCD patients with HIV infection and compared their antiviral innate and iron regulatory factors to SCD patients without HIV-1 infection. METHODS: PBMCs were isolated from whole blood of SCD patients without and with HIV-1 infection (SCD HIV+), HIV+ participants and healthy controls. Illumina NextSeq 500 was used for RNA Seq analysis. Normalized gene counts were used for gene set enrichment analysis (GSEA). Plasma cytokines were analyzed on Bio-Plex 200. RESULTS: GSEA of antiviral genes in SCD versus controls showed strong innate antiviral gene expression in SCD PBMCs (NES=0.91). The top 5 genes included IFITM3, MX2, IFI16, NFKBA and APOBEC3A. Iron regulatory genes were also highly expressed in SCD PBMCs comparing to controls (NES=1) and included BMP6, TFRC, TFR2, NCOA4, ERFE, FTH1 and HAMP. GSEA analysis showed strong upregulation of heme metabolism (NES = 1.21), IL-6 signaling (NES=1.12), hypoxia (NES=1.10), TNFα signaling (NES=1.28) and inflammatory response (NES=1.05). Innate antiviral factors (NES=0.68) and iron regulatory factors (NES=0.82) were upregulated in SCD compared to SCD patients with HIV-1 infection. SCD patients had statistically lower levels of hemoglobin and hematocrit compared to SCD HIV+ group and higher levels of IL-1β and IL-6. CONCLUSION: Our study shows that SCD patients have upregulated levels of innate antiviral response and also upregulated iron metabolism. The SCD patients with HIV-1 infection were hematologicaly closer to the non-infected individuals, demonstrating less pronounced expression of innate antiviral factors and less upregulated iron metabolism. Our findings indicate that HIV-1 infection might occur in SCD patients with less severe SCD manifestation. This work was supported by NIH grants 1R01HL125005, 5U54MD007597, 1P30AI117970-06 and 1SC1HL150685. George Washington University SPH Genomics Core conducted sequencing. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. The study was a retrospective cohort study (study period 2004-2018). Cases of HIV+and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV+controls without SCD (HIV+/SCD-). Thirty-five HIV+/SCD+subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD+had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P=0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD+and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan-Meier analysis showed a slower rate of treatment failures in the HIV+/SCD+cohort (P=0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD+cohort showed a more rapid rise and higher total CD4 count (P=0.012, regression analysis). The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD+achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.

Increased Iron Export By Ferroportin Induces Restriction of HIV-1 Infection in Sickle Cell Disease By SAMHD1

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Cancer Incidence in Sickle Cell Disease:an Institutional Experience

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

Background:Bacterial infections are a frequent cause of acute morbidity and sometimes mortality in sickle cell disease (SCD). Splenic dysfunction alone does not explain the susceptibility to specific organisms e.g., Staphylococcus aureus and Klebsiella as shown in some studies; suggesting that the splenic dysfunction is not the only explanation and that neutrophil dysfunction may be present. Neutrophils destroy microbes by producing a burst of reactive oxygen species (ROS) (respiratory burst) in response to bacterial components, as well as to phorbol‐myristate‐acetate (PMA). Some studies have shown that the state of chronic hemolysis in SCD impairs the ability to develop neutrophils to mount a bactericidal oxidative burst, and hence increasing susceptibility to bacterial infections.Aims:to assess the neutrophil oxidative burst in SCD patients and explore the relation to markers of hemolysis.Methods:Twenty‐seven hydroxyurea naïve children and adolescents with SCD (mean age 11.1 ± 3.9 years) were enrolled from Pediatric Hematology Clinic at Ain Shams University Children's Hospital. They were compared to 26 age‐ and sex‐matched healthy controls. Patients were studied stressing on transfusion history, chelation therapy, serum ferritin, hematological profile, markers of hemolysis and serum haptoglobin. Neutrophil oxidative burst assay was performed using DHR based flow cytometry.Results:Eleven (40%) out of the 27 patients had HBSS while 16 (60%) patients were sickle thalassemias. Six patients (22.2%) were splenectomized. Severe vaso‐occlusive crisis and acute chest syndrome were found in 22.2% and 18.5% of patients, respectively. Four (14.8%) patients had evidence of stroke. Bone fractures and avascular necrosis were found in 5.5% and 11.1 % of patients, respectively. Most of the studied patients were on chelation therapy, either as monotherapy or combined chelation (37% each). White blood cell count and reticulocytic count were significantly higher in SCD patients as compared to healthy controls (P = 0.03 and <0.01 respectively). All subjects, whether SCD or controls showed a normal neutrophil oxidative burst response to PMA‐stimulation. Unstimulated and PMA stimulated rhodamine fluorescence were comparable in SCD patients and controls, indicating normal basal production of reactive oxygen species, and normal oxidative burst in SCD patients (P = 0.09). We did not demonstrate any correlation between markers of hemolysis including reticulocytic count, indirect bilirubin, LDH, serum haptoglobin and DHR response in the SCD group.Summary/Conclusion:Neutrophils in SCD patients can mount a normal oxidative burst in response to PMA stimulation. This data excludes the role of impaired neutrophil oxidative burst as a risk for bacterial infections in SCD.

Splenic and Liver Involvement in Sickle Cell Disease