Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans

镰状细胞病和镰状细胞性状对非洲人和非裔美国人 HIV-1 感染的保护作用

• 批准号: 10589752
• 负责人: SERGEI NEKHAI
• 金额: $ 68.41万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589752
• 关键词: Abnormal Hemoglobins; Affect; Africa South of the Sahara; African; African American population; Alleles; Antiviral Response; CD8B1 gene; CDK2 gene; Case/Control Studies; Cells; Chronic; Chronic Disease; Clinic; Data; Development; Erythrocytes; Fetal Hemoglobin; Frequencies; Gene Expression; Genes; Genetic Transcription; Globin; Grant; HIV; HIV-1; HLA-B Antigens; Hematology; Heme; Hemoglobin; Hemoglobinopathies; Hemolysis; Hemolytic Anemia; Hepatic; Human immunodeficiency virus test; Hypoxia; Individual; Infection; Inherited; Innate Immune Response; Interferon alpha; Interferon-beta; Interferons; Iron; Iron Chelation; Low Prevalence; Macrophage; Measures; Mediating; Minority Groups; Mission; Molecular; Mus; Mutation; Nigerian; Participant; Patient Recruitments; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phosphorylation; Phylogeny; Production; Protein Dephosphorylation; Protein Export Pathway; Proteins; Public Health; Race; Research; Reverse Transcription; Risk; Sickle Cell; Sickle Cell Anemia; Sickle Cell Trait; Sickle Hemoglobin; T-Lymphocyte; TRIM Gene; Testing; The Multicenter AIDS Cohort Study; Therapeutic; United States National Institutes of Health; Universities; Up-Regulation; Viral; Viral Load result; Virus; Woman; arm; cohort; disparity reduction; dual diagnosis; hepcidin; in vivo; infection rate; inflammatory marker; iron metabolism; male; metal transporting protein 1; minority health; minority health disparity; monocyte; mouse model; novel; overexpression; prevent; screening; sickling; trait; transcriptome sequencing

Sickle cell disease (SCD) is an inherited hemoglobinopathy that leads to sickling of red blood cells and the development of chronic hemolytic anemia. SCD patients have lower risk for HIV-1 infection, but its underlying molecular mechanisms are not well understood. We recently showed that changes in iron metabolism leads to upregulation of innate immune response and prevent ex vivo HIV-1 infection of PBMCs obtained from SCD patients. Our working hypothesis is that hemolysis-mediated upregulation of ferroportin expression and iron export in SCD leads to the inhibition of HIV-1 replication. We further hypothesize that macrophage processing of abnormal sickle hemoglobin leads to interferon-β production and stimulation of antiviral response. What is yet unclear is whether SCD or sickle cell trait triggers an overall antiviral state or whether HIV-1 is controlled at post infection stage. To answer these questions, we will investigate HIV-1+ SCD patients and cohort of HIV-1+ sickle cell trait individuals to include males and Africans. We will also utilize mouse model of SCD to analyze EcoHIV-1 infection in vivo. In Specific Aim 1, we will analyze HIV-1 restriction in HIV-1+ SCD individuals. We will analyze the effect of SCD on HIV-1 infection in SCD HIV-1+ patients recruited from Howard University and Montefiore clinics. We will analyze their hematological and virological parameters and test host genes expression using RNA-Seq analysis. We will analyze their HIV-1 phylogeny, HLA-B alleles and inflammation markers. In Specific Aim 2, we will determine the effect of sickle cell trait on HIV-1 infection in African Americans and Africans and viral load in African Americans from WIHS, Multicenter Cohort AIDS Study (MACS), and a Nigerian cohort. We will conduct multivariable analysis to determine the effect of the trait on viral load, relationship to CD4/CD8 counts and levels of proteins involved in iron metabolism and HIV-1 restriction. We will also conduct a case control study to analyze HIV-1phylogeny and the effect of iron and inflammation markers on HIV-1 progression. In Specific Aim 3, we will analyze molecular mechanisms of HIV-1 inhibition in SCD and sickle cell trait. We will analyze expression of host HIV-1 restriction factors in monocyte- derived macrophages treated with HbSS and HbAS hemoglobin and test selected factors in ex vivo HIV-1 infection of PBMCs derived from SCD patients and HIV-1+ sickle cell trait participants from WIHS and MACS cohorts. We will also test HIV-1 infection in SCD and trait mouse models using EcoHIV virus that infects mice and leads to the latent HIV-1 infection in T cells and macrophages.The proposed research will elucidate the molecular mechanisms of HIV-1 inhibition in the settings of SCD and sickle cell trait, which could lead to novel anti-HIV-1 therapeutics based on the concept of HIV-1 restriction mediated by hemolysis and interferon induction by sickle cell hemoglobin.

镰状细胞病(SCD)是一种遗传性血红蛋白病，会导致红细胞呈镰状，而 慢性溶血性贫血的发展。SCD患者感染HIV-1的风险较低，但其潜在的 分子机制还不是很清楚。我们最近发现，铁代谢的变化会导致 SCD患者外周血单个核细胞上调先天免疫应答及预防HIV-1体外感染 病人。我们的工作假设是，溶血介导了铁蛋白表达和铁的上调 SCD中的出口导致HIV-1复制的抑制。我们进一步假设巨噬细胞处理 异常的镰状血红蛋白导致干扰素-β的产生和抗病毒反应的刺激。是什么 然而，尚不清楚SCD或镰状细胞特性是否触发整体抗病毒状态，或者HIV-1是否被控制在 感染后阶段。为了回答这些问题，我们将调查HIV-1+SCD患者和HIV-1+队列 镰状细胞特征个体包括男性和非洲人。我们还将利用SCD的小鼠模型进行分析 体内感染EcoHIV-1。在具体目标1中，我们将分析HIV-1+SCD患者中HIV-1的限制性。 我们将分析SCD对从霍华德大学招募的SCD HIV-1+患者HIV-1感染的影响 和蒙特菲奥雷诊所。我们将分析他们的血液学和病毒学参数，并测试宿主基因 使用RNA-Seq分析进行表达。我们将分析他们的HIV-1系统发展史、人类白细胞抗原B等位基因和炎症 记号笔。在特定的目标2中，我们将确定镰状细胞特性对非洲HIV-1感染的影响 来自WIHS的美国人、非洲人和非裔美国人的病毒载量，多中心队列艾滋病研究 (Mac)和一个尼日利亚队列。我们将进行多变量分析，以确定性状对 病毒载量与CD4/CD8计数和铁代谢及HIV-1相关蛋白水平的关系 限制。我们还将进行一项病例对照研究，以分析HIV-1的发生发展以及铁和铁的作用。 HIV-1进展的炎症标志物。在具体目标3中，我们将分析HIV-1的分子机制 对SCD和镰状细胞性状的抑制。我们将分析宿主HIV-1限制性因子在单核细胞中的表达- HbSS和HbAS处理来源的巨噬细胞及体外检测HIV-1相关因子 系统性红斑狼疮患者外周血单个核细胞感染及WIHS和MACs中HIV-1+镰状细胞特性研究 一群人。我们还将使用感染小鼠的EcoHIV病毒在SCD和特征小鼠模型中测试HIV-1感染 并导致T细胞和巨噬细胞中潜伏的HIV-1感染。 在SCD和镰状细胞特性背景下抑制HIV-1的分子机制，这可能导致新的 基于溶血和干扰素抑制HIV-1概念的抗HIV-1治疗 由镰状细胞血红蛋白诱导。