scholarly journals LIC-R2 Values Predict Severity of SCD: Baseline Data from Licnet-S

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4810-4810
Author(s):  
Rosario Di Maggio ◽  
Angela Vitrano ◽  
Carmelo Fidone ◽  
Alessandra Quota ◽  
Daniela Fiorino ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Iron Absorption ◽  
Conflicts Of Interest ◽  
Severe Disease ◽  
Predictor Variable ◽  
Clinical Findings ◽  
Cell Disease ◽  
Intestinal Iron Absorption ◽  
The Relationship

Introduction Sickle cell disease (SCD) is a monogenic, yet highly phenotypically variable disease with multisystem pathology. HbS is prone to polymerization upon deoxygenation, and this property underlies all the pathophysiology of SCD. The net result is a chronic hemolytic anemia, with intravascular and extravascular components, and a tendency for microvascular obstruction or vaso-occlusion (VOC). The ability to predict ''severe disease'' depends on the ability to define it specifically and reproducibly. Many genetic, clinical and laboratory modifiers have been suggested as possible predictors of a "severe disease". Despite of this wealth of data the modelling of predictor variable continues to be difficult (Quinn et al, 2016). Considering that the hallmark of SCD is the chronic hemolitic anemia causing increasing of gastro-intestinal iron absorption, our aim was to evaluate if LIC-R2 (Ferriscan) determination may be related with phenotype severity of SCD. Methods This was a retrospective study of patients with SCD attending 7 Italian centres participating in the LICNET-S (Liver Iron Cutino NETwork in Sickle Cell Disease), collected at the Campus of Hematology Franco and Piera Cutino, AOOR Villa Sofia-V. Cervello (Palermo, Italy). The LICNET-S protocol was established on June 2018 by Foundation Franco and Piera Cutino of Palermo and approved by our Ethics Committee on 4, July 2018. This analysis included data from LIC-R2 for those patients presenting between July 2018 and July 2019. The MRI-R2 used protocol was that of St Pierre et al, 2005. Retrieved information included laboratory and clinical findings. These are shown as mean±sd and percentages. A linear regression model (LRM) (Draper & Smith, 1998) was used to study the correlation between LIC-R2 and some potential indicators of phenotype severity. All statistical analyses were performed using Stata 12 (StataCorp, College Station, TX, USA). Results Overall 65 patients (32 (49.3%) females) whom 16 patients with S/S, 15 with S/beta+ tahalseemia and 34 with S/beta0 thalassemia were enrolled in the study. Table 1 shows summary of the main clinical findings included in the study to evaluate the LIC-R2 predictivity based on SCD phenotype severity. Table 2 shows the results of the LRM analysis. The variables statistically significant were the number of the VOC, the Aseptic Avascular Necrosis (AVN) and the Chelation Treatment (CT) (Table 2). However, transfusion regimen was not related with LIC-R2 value, suggesting that chronic hemolitic anemia causing increasing of gastro-intestinal iron absorption rather than transfusion treatment was the main determinant in the LIC-R2 values. This issue is supported by the report of high LIC-R2 in non transfused patients with SCD (Yassim et al, 2017). Table 2 shows even the relationship between the impairment of the single indicator (VOC, AVN, CT) and the LIC-R2 value. All other laboratory and main clinical findings included in Table 2 were not statistically significant. The value of VOC in determining phenotype severity is well known. AVN is a consequence of a chronic ischaemia with inflammatory process evolving at the same time as medullary osteoblastic activity (Mukizi-Musaka et al, 2010). Therefore, it may be related with the chronic hemolitic anemia condition in SCD. Finally, the relationship between CT and LIC-R2 may be explained considering that patients with higher iron body burden are those who received earlier chelation treatment. Conclusions This study suggests, as LIC-R2 value is a strong predictive indicator of phenotype severity in SCD. Probably, this is due because of LIC-R2 is related both with acute and chronic hemolitic anemia of SCD causing an increase, during the years, of gastro-intestinal iron absorption. Therefore, the possibility of preventing VOC, even using new anti-sickling drugs, should be hardly pursued. Disclosures No relevant conflicts of interest to declare.

scholarly journals Iron Overload in the Face of Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-38-SCI-38
Author(s):  
Yatrik Shah
Keyword(s):  
Transcription Factors ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Absorption ◽  
Conflicts Of Interest ◽  
Iron Accumulation ◽  
Cell Disease ◽  
Divalent Metal Transporter 1 ◽  
Tissue Iron

Abstract Several distinct congenital disorders can lead to tissue-iron overload with anemia including β-thalassemia and sickle cell disease. We show that intestinal absorption of iron is highly increased and significantly contributes to tissue iron accumulation in these disorders. The present work describes a novel pathway by which oxygen sensing transcription factors are highly upregulated in iron overload anemias and are subsequently essential for the increase intestinal iron absorption. Oxygen signaling is mediated through well-conserved hypoxia driven transcription factors, hypoxia-inducible factor (HIF)1a and HIF2a. In the intestine, HIF2a directly activates divalent metal transporter 1 (DMT1), duodenal ferric reductase (DcytB), and Fpn1, which are iron transporters critical for adaptive changes in iron absorption. We demonstrate that HIF2a and its downstream target gene, DMT1 are essential for iron accumulation in mouse models of β-thalassemia and sickle cell disease. Furthermore, studies of thalassemic mouse model with established iron overload demonstrated that loss of intestinal HIF2a and DMT1 signaling led to decreased tissue iron accumulation in the livers. Interestingly, disrupting intestinal HIF2a not only improves tissue iron accumulation, but a marked improvement of anemia was also observed. These novel findings suggests that inhibition of HIF2a signaling pathway could be a novel and robust treatment strategy for several conditions that cause iron overload with anemia. Disclosures No relevant conflicts of interest to declare.

Predictors of Length of Stay and Time to Readmission in Adult Patients with Sickle Cell Disease: A Single Institution Experience in the UK

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2130-2130
Author(s):  
Emma Drasar ◽  
Sarah A Bennett ◽  
Nisha Vasavda ◽  
Swee Lay Thein
Keyword(s):  
Sickle Cell Disease ◽  
Length Of Stay ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Severe Disease ◽  
Adult Patients ◽  
Rank Test ◽  
Continuous Variables ◽  
Cell Disease ◽  
The Uk

Abstract Abstract 2130 Background: Sickle cell disease (SCD) is characterised by chronic hemolytic anemia and recurrent acute clinical events. The most common cause of hospital attendance is acute pain and in our patient population it accounts for 84% of all admissions. Financial pressure has led to an interest in the factors affecting length of stay (LOS) and readmission rate (RAR). The 30 day RAR has been highlighted by the UK government as a care standard. In the UK general hospital population the 30 day RAR is 6.5% of all admissions with an estimated cost to the NHS of £1.6 billion/year. A study in the US showed RAR to be 33.4% in the sickle cell population, with a lower rate in children (23%). In SCD multiple factors have been postulated to influence RAR and LOS including patient demographics (e.g. sex and socio-economic status), and hospital variables (hospital status). This retrospective study aims to assess the clinical factors which affect LOS and RAR in the SCD population at a busy London teaching hospital. Methods: The study group consisted of 505 adult patients who were recorded on the King's College Hospital Sickle Cell Database between 1st of January 2009 and 31st of December 2010. The Electronic Patient Record was examined for patient ward, dates of admission and discharge, time to hematology review and time to readmission (TTR) were calculated. Patients with SCD are primarily cared for by hematology however, out of hours, patients may be initially admitted under another medical team and then have their care transferred to the hematology team. Red blood cell units transfused and time to first transfusion were recorded for each event. Data were analyzed statistically using t-tests or Mann-Whitney-U for binary variables (e.g. sex), and Spearman's rank test for continuous variables (e.g. age). TTR was analysed as a binary (≤30 days or >30 days) and continuous variable. Results: The cohort of 505 patients included 299 (60%) female and 206 (40%) male. Mean age was 35 years (range 18–80). 315 patients (63%) had HbSS and 9 (2%) had HbSβ0, 160 (32%) HbSC and 21 (4%) HbSβ+. 207 of the 505 patients had a total of 586 admissions over the study period (mean 3 admissions/ patient, range 1–19). 156 (75%) of the admitted patients had HbSS or HbSβ0 (SCA), 47 (23%) HbSC and 4 (2%) HbSB+. Age of the admission group ranged from 18–80 years (mean 33). LOS ranged from 0 – 116 (mean 7, median 5) days. 45% (264/586) of all admissions could be accounted for by 7% of patients and 83% (489/586) of admissions were patients with SCA. There were 279 readmissions during the study period, (100 [36%] within 30 days) by 83 patients. 72/83 (87%) of readmitted patients had SCA compared to 10/83 (4%) HbSC. Of readmissions within 30 days 95% were by patients with SCA. Further analysis was limited to the SCA group. Female patients had a significantly longer LOS (median 5 days) than male patients (4 days) p = 0.002. There was significant correlation between LOS and TTR (R = 0.11 p=0.03). Patients admitted directly under the hematology team or who were transferred to their care had a significantly longer LOS (5 days) than those who were never admitted under hematology (2 days) p <0.0001. Patients admitted to the hematology wards also had a significantly longer LOS (5 days) compared with those on wards belonging to other specialities (4 days) p = 0.008. Delay to review by the hematology team correlated significantly with increased LOS (R = 0.12 p = 0.02) as does delay to transfusion (R = 0.45 p <0.0001). Interestingly delay to review by the hematology team appears to delay transfusion (R = 0.23 p = 0.011). The number of transfused units also correlated significantly with both LOS (R=0.39 p <0.0001) and an increase in time to readmission (R=0.136 p=0.008). Conclusion: There are a disproportionate number of admissions by patients with SCA who also had a greater proportion of readmissions, reflecting the relative severity of this condition compared to HbSC. These results also highlight that there is a small cohort of patients with relatively more severe disease who have an increased LOS and increased requirement for intervention in the form of transfusion. Delay to review and therefore the decision to transfuse also appears to increase LOS, although involvement of the hematology team does not reduce it. Increased LOS and receiving transfusion treatment do appear to be associated with a delay in time to readmission. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antiphospholipid Antibodies in Sickle Cell Disease: A Systematic Review and Exploratory Meta-Analysis

2021 ◽  
Vol 27 ◽  
pp. 107602962110029
Author(s):  
Mira Merashli ◽  
Alessia Arcaro ◽  
Maria Graf ◽  
Matilde Caruso ◽  
Paul R. J. Ames ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Antiphospholipid Antibodies ◽  
Meta Analysis ◽  
Age Groups ◽  
Anticardiolipin Antibodies ◽  
Cell Disease ◽  
Pooled Prevalence ◽  
The Relationship

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

scholarly journals Clinical findings associated with homozygous sickle cell disease in the Barbadian population – do we need a national SCD registry?

2014 ◽  
Vol 7 (1) ◽  
Author(s):  
Kim R Quimby ◽  
Stephen Moe ◽  
Ian Sealy ◽  
Christopher Nicholls ◽  
Ian R Hambleton ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Findings ◽  
Cell Disease ◽  
Homozygous Sickle Cell Disease

scholarly journals Validity and Reliability of Sickle Cell Self-efficacy Scale

2014 ◽  
Vol 8 (4) ◽  
pp. 31-35
Author(s):  
Sheyda Javadipour ◽  
Shiva Javadipour ◽  
Bijan Keikhaeidehdezi ◽  
Meymanat Akbari
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Self Efficacy ◽  
Research Center ◽  
Cell Disease ◽  
Validity And Reliability ◽  
Medical Sciences ◽  
Functional Activities ◽  
Rehabilitation Research ◽  
The Relationship

Correction: On 20/08/2014 the spelling of the third author was changed from Bijan Keykhah DehdeziTO Bijan Keikhaeidehdezi.Correction: On 20/08/2014 the affiliation of the first author was changed fromMusculoskeletal Rehabilitation Research Center, Jundishapur University of Medical Sciences of Ahvaz, IranTO Musculoskeletal Rehabilitation Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Abstract:Background: psychometric properties of a 9-item self-appraisal scale for studying self-efficacy in sickle cell disease was evaluated in order to survey people’s comprehension of their capabilities to be engaged in functional activities of daily living who were suffering from sickle cell disease and in order to manage syndromes.Methods: the participants of this study were aged between 11-19 years with sickle cell disease under treatment for at least one year.Result: reliability analysis showed the internal consistency and correlation coefficient of the scale to be acceptable values. Construct validity analysis showed moderate positive correlation between the scores obtained using Sickle Cell Self-Efficacy Scale and those obtained using Mental Components Scale of SF36. There is a weak correlation between the score obtained from SCSES and that of Physical Components Scale of SF36.Conclusion: this scale can be used in the future for future studies on self-efficacy and also to find the relationship between this component and other components.DOI: http://dx.doi.org/10.3126/ijls.v8i4.10931

scholarly journals Case Report: Acute Stroke in Young Adult Patient with Moyamoya Syndrome Secondary to Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Oladipo Cole ◽  
Asia Filatov ◽  
Javed Khanni ◽  
Patricio Espinosa
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Moyamoya Disease ◽  
Conflicts Of Interest ◽  
Acute Chest Syndrome ◽  
African American Female ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Radiographic Findings

Moyamoya disease, well described in literature, is a chronic cerebrovascular occlusive disorder. It is characterized by progressive stenosis/occlusion of the terminal portions of the internal carotid arteries (ICA) and the proximal portions of the middle cerebral arteries (MCA). Less frequently described is Moyamoya syndrome, the name given to radiographic findings consistent with Moyamoya disease, but with an identifiable cause. The diseases associated with Moyamoya Syndrome include Sickle Cell Disease (SCD), Thalassemias, and Down's Syndrome to name a few. Common complications of Moyamoya include both ischemic and hemorrhagic strokes. Upon literature review, Moyamoya syndrome caused by SCD is not well described. When it is, the discussion is centered around the pediatric patient population and surgical management. Our case report describes a 22-year-old African American female with SCD who initially presented with Acute Chest Syndrome. Her hospital course was complicated by development of overt debilitating neurologic deficits. Subsequently, she was found to have Moyamoya Syndrome on neuroimaging. She was successfully treated with medical management without any surgical intervention. This case highlights the necessity of thorough examination, differential diagnosis, imaging findings, and consideration of predisposing syndromes in the work-up for Moyamoya syndrome; especially individuals with Sickle Cell Disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Victoria Brooks ◽  
Oluwalonimi Adebowale ◽  
Victor R. Gordeuk ◽  
Sergei Nekhai ◽  
James G. Taylor
Keyword(s):  
Risk Factors ◽  
Alkaline Phosphatase ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Severe Disease ◽  
Case Control ◽  
Red Cell ◽  
Cell Disease ◽  
History Of

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with &gt;10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

scholarly journals Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Satish Maharaj ◽  
Simone Chang ◽  
Karan Seegobin ◽  
Marwan Shaikh ◽  
Kamila I. Cisak
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Acute Chest Syndrome ◽  
Adult Males ◽  
Cell Disease ◽  
Unequal Variances ◽  
Recorded Data

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT&gt;0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interferon Induction By HbS, SERINC5 Upregulation and Reduction of HIV-1 Nef and AP2 Contribute to HIV-1 Restriction in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Namita Kumari ◽  
Marina Jerebtsova ◽  
Songping Wang ◽  
Sharmin Diaz ◽  
Sergei Nekhai
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Interferon Response ◽  
Cell Disease ◽  
Restriction Factors ◽  
Peripheral Blood Mononuclear ◽  
Hiv 1

Concerted action of numerous positively acting cellular factors is essential for Human immunodeficiency virus type 1 (HIV-1) replication but in turn is challenged by anti-viral restriction factors. Previously we showed that ex vivo one round HIV-1 replication and replication of fully competent T-tropic HIV-1(IIIB) is significantly reduced in peripheral blood mononuclear cells (PBMCs) obtained from patients with Sickle Cell Disease (SCD). Further, we identified and confirmed CDKN1A (p21) and CH25H as host restriction factors expressed in SCD PBMCs that may contribute to the HIV-1 inhibition, in addition to the previously reported SAMHD1 and IKBα. Since CH25H is an interferon stimulated gene (ISG), we analyzed IRFs and interferon expression in SCD PBMCs. Higher levels of IRF7 and IFNβ mRNA were observed in SCD PBMCs compared to controls. We probed further to ascertain if hemin or sickle Hb was responsible for interferon response. We found upregulation of IFNβ in THP-1 - derived macrophages treated with lysates of HbSS RBCs or purified HbS as compared to untreated or HbA treated controls. HbSS RBCs lysates and purified HbS inhibited HIV-1 gag mRNA expression in monocyte-derived macrophages infected with HIV-1(Ba-L). Recent clinical study showed increased levels of CD4 in HIV-1 infected SCD patients in Africa. Thus we analyzed CD4 levels in HIV-1 IIIB infected SCD PBMCs, and found them to be higher compared to controls. Levels of HIV-1 nef mRNA, that controls CD4 expression was lower in HIV-1 IIIB infected SCD PBMCs. As Nef counteracts SERINC3/5 restriction factor, we analyzed its expression as well as the expression of AP2 clathrin adaptor that is required for Nef mediated internalization of CD4. AP2 expression was lower and SERINC5 expression was higher in SCD PBMCs. CONCLUSIONS: SCD PBMCs could resist HIV-1 infection because of the increased IFNβ production by macrophages exposed to HbSS or sickle cell RBCs. SCD PBMC have increased levels of SERNIC5 and lower levels of HIV-1 Nef and host AP2 expression that, culumlatively, can increased CD4 levels and lead to the overall improved immunological health of SCD patients. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 1SC1HL150685, 5U54MD007597, 1UM1AI26617 and P30AI087714). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures No relevant conflicts of interest to declare.

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