Effects of HIV and ART on myelination in the adolescent

HIV 和 ART 对青少年髓鞘形成的影响

• 批准号: 10258486
• 负责人: JUDITH B GRINSPAN
• 金额: $ 86.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10258486
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Age of Onset; Anisotropy; Behavioral; Brain; CD4 Positive T Lymphocytes; Caring; Cell Count; Cell Differentiation process; Clinical; Cognitive; Data; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Fumarates; Functional disorder; Gene Expression; Genes; HIV; HIV Infections; HIV antiretroviral; HIV therapy; HIV-1; HIV-associated neurocognitive disorder; HIV-infected adolescents; Human; Image; Impaired cognition; In Vitro; Infection; Knowledge; Laboratories; Learning; Lesion; Lipids; Lysosomes; Magnetic Resonance Imaging; Measures; Mediating; Memory; Myelin; Myelin Proteins; Myelin Sheath; Neuraxis; Neurites; Nucleosides; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Rattus; Reverse Transcriptase Inhibitors; Rodent Model; Role; Stress; Structure; Synaptic plasticity; Tenofovir; Therapeutic Effect; Thick; Time; Transcript; Transgenic Organisms; Treatment-related toxicity; United States; Up-Regulation; Viremia; Virus; Virus Replication; age related; antiretroviral therapy; base; behavioral impairment; biological adaptation to stress; cohort; density; emtricitabine; gray matter; in vitro Model; in vivo; indexing; macrophage; meetings; morphometry; motor impairment; myelination; neuroimaging marker; neuroinflammation; non-invasive monitor; oligodendrocyte precursor; pre-exposure prophylaxis; precursor cell; prevent; protein expression; remyelination; success; synaptic pruning; transcriptome; white matter; young adult

Project Summary Adolescents account for a disproportionately high percentage of new HIV infections each year: in 2018, 30% of all new global infections were among 15-25 year-olds, and 21% of all new United States infections were among 13-24 years-olds 2-4. However, we know little about the effects of new infection and therapy on the developing brain in this critical time frame. Limited studies on HIV+ 18-24 year-olds on and off antiretroviral therapy (ART) demonstrate that up to 65% develop behavioral, cognitive and motor impairments meeting the criteria for HIV associated neurocognitive disorder (HAND) 5,6, a proportion higher than that seen in older HIV+ adult counterparts despite lower viremia, higher CD4+ T-cell counts, and shorter durations of infection in adolescents 7. A major gap in our knowledge is the mechanistic basis of this dysfunction in the developing central nervous system (CNS). The effect of virus-mediated and/or ART toxicities on normal myelination and synaptic pruning in the adolescent and young adult brain is unknown. It is well documented that functionally critical development of white matter (WM) and synaptic plasticity continues until the mid-twenties in humans 8. Interestingly, WM deficits, including myelin lesions, decreased myelin sheath thickness, and abnormal myelin protein expression, are among the persistent pathologic findings in HIV+ adults with HAND 1,9-11 Consistent with pathologic findings, transcriptome analyses of cortical gray matter (GM) and WM from HIV+ adults, both ART- naïve and ART-treated, have revealed decreased expression of genes associated with oligodendrocyte (OL) differentiation and myelination 12,13. We have shown HIV-associated neuroinflammation inhibits OL maturation through upregulation of the integrated stress response (a pathway shown to be dysregulated in the CNS of HIV+ patients) 14,15. Further, data from our laboratory also suggest that a subset of ARV drugs themselves can disrupt differentiation of OL precursor cells in vitro and remyelination in vivo 16-18. An independent effect of ARV drugs on WM pathology is clinically important not only in the care of HIV+ adolescents, but also in uninfected adolescents who use pre-exposure prophylaxis (PrEP), a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), to prevent HIV infection. Our preliminary data indicate that several ARV drugs, including FTC and TDF, inhibit the progression of OL maturation in vitro through lysosomal dysfunction suggesting a role for organellar stress. Thus, we hypothesize that HIV, ART and PrEP disrupt developmental myelination via organellar stress contributing to the multifaceted CNS deficits observed in adolescents and young adults. We propose to: 1) Determine the mechanisms by which HIV- induced neuroinflammation disrupts OL maturation in adolescents, 2) Determine the role of lysosome dysfunction in ART-induced changes in OL maturation in rodent models of adolescence and young adulthood, and 3) Compare OL maturation and myelination measures in Aims 1 and 2 to magnetic resonance imaging measures of WM volume and integrity in adolescent rats and a pre-existing cohort of adolescent humans.

项目概要 每年新发艾滋病毒感染者中青少年所占比例过高：2018 年，青少年占 30% 全球所有新感染病例均集中在 15-25 岁人群中，美国所有新感染病例中 21% 是 13-24岁2-4岁。然而，我们对新感染和治疗对发育中的疾病的影响知之甚少。 大脑在这个关键的时间范围内。对接受和停止抗逆转录病毒治疗 (ART) 的 18-24 岁 HIV+ 患者进行的有限研究 表明高达 65% 的人出现符合 HIV 标准的行为、认知和运动障碍 相关神经认知障碍 (HAND) 5,6，比例高于老年 HIV + 成人同行 尽管青少年病毒血症较低、CD4+ T 细胞计数较高且感染持续时间较短 7。 我们知识上的差距是发育中的中枢神经功能障碍的机制基础 系统（中枢神经系统）。病毒介导和/或 ART 毒性对正常髓鞘形成和突触的影响 青少年和年轻人大脑的修剪尚不清楚。有据可查的是，功能关键 人类白质 (WM) 和突触可塑性的发育持续到二十多岁 8. 有趣的是，WM 缺陷，包括髓鞘病变、髓鞘厚度减少和髓鞘异常 蛋白表达，是患有 HAND 1,9-11 的 HIV+ 成人中持续存在的病理学发现之一 HIV+ 成人的皮质灰质 (GM) 和 WM 的病理结果、转录组分析，均为 ART- 首次接受 ART 治疗后，发现与少突胶质细胞 (OL) 相关的基因表达降低 分化和髓鞘形成12,13。我们已经证明 HIV 相关的神经炎症会抑制 OL 的成熟 通过上调综合应激反应（艾滋病毒+的中枢神经系统中显示出失调的途径） 患者）14,15。此外，我们实验室的数据还表明，一部分抗逆转录病毒药物本身可以破坏 OL 前体细胞的体外分化和体内髓鞘再生16-18。 ARV 药物对患者的独立影响 WM 病理学不仅在 HIV + 青少年的护理中具有重要的临床意义，而且在未感染的青少年中也具有重要意义 使用暴露前预防 (PrEP)（两种核苷逆转录酶抑制剂的组合）的人， 恩曲他滨 (FTC) 和富马酸替诺福韦二吡呋酯 (TDF)，用于预防 HIV 感染。我们的初步数据 表明几种 ARV 药物，包括 FTC 和 TDF，通过以下方式抑制体外 OL 成熟的进程： 溶酶体功能障碍表明细胞器应激的作用。因此，我们假设 HIV、ART 和 PrEP 通过细胞器应激破坏发育性髓鞘形成，导致多方面的中枢神经系统缺陷 在青少年和年轻人中观察到。我们建议： 1) 确定 HIV- 诱导的神经炎症扰乱青少年 OL 成熟，2) 确定溶酶体功能障碍的作用 ART 诱导的青春期和青年期啮齿动物模型中 OL 成熟的变化，以及 3) 将目标 1 和 2 中的 OL 成熟和髓鞘形成测量与磁共振成像测量进行比较 青春期大鼠和预先存在的青春期人类群体的 WM 体积和完整性。