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

摘要 目前的人类免疫缺陷病毒（HIV）抗逆转录病毒疗法（ART）在降低病毒载量方面是有效的，但 治疗经常伴随着严重的副作用。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）。一些研究支持叶酸和 同型半胱氨酸（HCY）是HIV相关血管AE和NAE常见修饰剂。具体来说，艾滋病毒- 感染的患者通常具有较低的血清叶酸和升高的HCY。此外，据报道，HCY水平 接受ART治疗的HIV感染患者的叶酸水平高于未接受ART治疗的HIV感染患者。 和HCY也被报道可以改变HIV感染者的神经损伤。一项临床研究报告称， 叶酸缺乏的患病率在HIV感染的神经精神病患者中最高;然而， 补充改善神经精神评估评分以及CD 4计数。我们建议测试 整合酶抑制剂（INI）：雷特格韦、度鲁特韦、埃替格韦、比替格韦和卡替格韦， 脑叶酸浓度和NAE。我们报告说，多种胰岛素是部分拮抗剂对叶酸 受体（FOLR 1）。已知FOLR 1蛋白影响血清叶酸、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降低， INIs和机制上至少部分由于FOLR 1-叶酸拮抗作用。此外，我们预计， 在生物化学测定中观察到的FOLR 1相互作用将在小鼠模型中产生脑叶酸缺乏症， 在人类细胞研究中的神经毒性。预计这些数据也将支持基于叶酸的缓解措施 减少人类ART相关NAE的策略。

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.