Pathogenic Linking of HIV Integrase Inhibitors, Folate Receptors, and Cerebral Folate Deficiency

HIV 整合酶抑制剂、叶酸受体和脑叶酸缺乏的致病联系

基本信息

批准号：
10023284
负责人：
Robert M Cabrera
金额：
$ 20万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023284
关键词：
Adverse event Anemia Animal Model Animals Apoptosis Binding Biochemical Biological Assay Blood Blood Vessels Brain Buffers CD4 Lymphocyte Count Calcium Carrier Proteins Cations Cell model Cells Cerebrospinal Fluid Cerebrum Chronic Clinical Clinical Research Data Diet Erythrocytes Folic Acid Folic Acid Antagonists Folic Acid Deficiency HIV HIV Infections HIV Integrase Inhibitors HIV Seropositivity HIV antiretroviral Homocysteine Human Human Cell Line Hyperhomocysteinemia In Vitro Incidence Individual Integrase Inhibitors Intervention Iron Link Membrane Metabolic Metabolism Molecular Molecular and Cellular Biology Mus Neurologic Pathogenicity Pathology Patients Pattern Pharmaceutical Preparations Physiological Plasma Prevalence Reporting Research Research Proposals Risk Role SLC19A1 gene Secondary to Serum Severities Structure of choroid plexus Testing Time Tissues Treatment Efficacy Viral Load result Vitamin B 12 Vitamins Work antiretroviral therapy base chelation clinical risk clinically relevant cytotoxicity experience folate-binding protein folic acid supplementation fortification gastrointestinal human tissue improved mouse model nerve injury neurobehavioral disorder neuropathology neuropsychiatry neurotoxicity prevent programs protein expression receptor relating to nervous system response side effect uptake

项目摘要

Abstract Current human immunodeficiency virus (HIV) antiretroviral therapy (ART) is effective at reducing viral loads, but treatment is frequently associated with significant side effects. Adverse events (AEs) reported with HIV ART include vascular, metabolic, and neurological adverse events (NAEs). Several studies support that folate and homocysteine (HCY) are common modifiers of HIV-associated vascular AEs and NAEs. Specifically, HIV- infected patients often have lower serum folate and elevated HCY. Additionally, HCY levels are reported to be higher in HIV-infected patients treated with ART compared to HIV-infected patients not exposed to ART. Folate and HCY are also reported to modify neural injury in HIV-infected individuals. A clinical study reported that the prevalence of folate deficiency is highest among HIV-infected neuropsychiatric patients; however, folate supplementation improved neuropsychiatric assessment scores as well as CD4 counts. We propose testing of integrase inhibitors (INIs): raltegravir, dolutegravir, elvitegravir, bictegravir, and cabotegravir, for impacts on cerebral folate concentrations and NAEs. We report that multiple INIs are partial antagonists against folate receptor (FOLR1). The FOLR1 protein is known to influence serum folate, HCY, and cerebral spinal fluid (CSF) folate concentrations. We hypothesize that serum folate and CSF folate concentrations are reduced by specific INIs and mechanistically due to, at least in part, FOLR1-folate antagonism. Furthermore, we expect that the INI- FOLR1 interactions observed in biochemical assays will produce cerebral folate deficiency in mouse models and neurotoxicity in human cellular studies. These data are also expected to support folate-based mitigation strategies to reduce ART-related NAEs in humans.

抽象的目前的人类免疫缺陷病毒 (HIV) 抗逆转录病毒疗法 (ART) 可有效减少病毒载量，但治疗常常伴随着显着的副作用。 HIV ART 报告的不良事件 (AE) 包括血管、代谢和神经系统不良事件 (NAE)。多项研究支持叶酸和同型半胱氨酸 (HCY) 是 HIV 相关血管 AE 和 NAE 的常见修饰因子。具体来说，艾滋病毒- 感染患者的血清叶酸通常较低，HCY 升高。此外，据报道，HCY 水平为与未接受 ART 的 HIV 感染患者相比，接受 ART 治疗的 HIV 感染患者的这一比例更高。叶酸据报道，HCY 和 HCY 也可以改善 HIV 感染者的神经损伤。一项临床研究报告称， HIV 感染的神经精神病患者中叶酸缺乏症的患病率最高；然而，叶酸补充剂改善了神经精神评估分数以及 CD4 计数。我们建议测试整合酶抑制剂 (INIs)：拉替拉韦、多替拉韦、埃替拉韦、比克替拉韦和卡博特拉韦，用于影响脑叶酸浓度和 NAE。我们报告多种 INI 是叶酸的部分拮抗剂受体（FOLR1）。已知 FOLR1 蛋白会影响血清叶酸、HCY 和脑脊液 (CSF) 叶酸浓度。我们假设血清叶酸和脑脊液叶酸浓度因特定的 INI 和机制至少部分归因于 FOLR1-叶酸拮抗作用。此外，我们预计 INI- 生化检测中观察到的 FOLR1 相互作用将导致小鼠模型中脑叶酸缺乏人类细胞研究中的神经毒性。这些数据预计也将支持基于叶酸的缓解措施减少人类 ART 相关 NAE 的策略。