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)在减少病毒载量方面是有效的，但 治疗常常伴随着显著的副作用。艾滋病毒抗逆转录病毒治疗报告的不良事件(AEs) 包括血管、代谢和神经不良事件(NAE)。几项研究支持叶酸和 同型半胱氨酸(HCY)是HIV相关血管病变和NAE的常见修饰物。具体来说，艾滋病毒- 感染患者的血清叶酸水平通常较低，HCY水平较高。此外，据报道，HCY水平为 接受抗逆转录病毒治疗的艾滋病毒感染患者比未接受抗逆转录病毒治疗的艾滋病毒感染患者更高。叶酸 和HCY也被报道可以改变HIV感染者的神经损伤。一项临床研究报告说， 在感染艾滋病毒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和CD4计数。我们建议测试 整合酶抑制剂(INI)：Raltegravir、Dolutegravir、elvitegravir、bitegravir和Cabotegravir，用于影响 脑叶酸浓度和NAE。我们报告多个INI是叶酸的部分拮抗剂。 受体(FOLR1)。已知FOLR1蛋白影响血清叶酸、同型半胱氨酸和脑脊液(CSF) 叶酸浓度。我们假设血清叶酸和脑脊液叶酸浓度是由特定的 至少部分是由于FOLR1-叶酸拮抗作用所致。此外，我们预计INI- 生化分析中观察到的FOLR1相互作用将在小鼠模型中产生脑叶酸缺乏和 人类细胞研究中的神经毒性。这些数据也有望支持基于叶酸的缓解 减少人类中与抗逆转录病毒药物相关的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.