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: 10556341
• 负责人: JUDITH B GRINSPAN
• 金额: $ 75万
• 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/10556341
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Age of Onset; Anisotropy; Anti-Retroviral Agents; Behavioral; Brain; CD4 Positive T Lymphocytes; Caring; Cell Count; Cell Differentiation process; Central Nervous System; Clinical; Cognitive; Data; Development; Diffusion Magnetic Resonance Imaging; Fumarates; Functional disorder; Gene Expression; Genes; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; HIV-infected adolescents; Human; Image; Impaired cognition; In Vitro; Infection; Knowledge; Laboratories; Learning; Lesion; Lipids; Lysosomes; Macrophage; Magnetic Resonance Imaging; Measures; Mediating; Memory; Myelin; Myelin Proteins; Myelin Sheath; Neurites; Nucleosides; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Rat Transgene; Rattus; Reverse Transcriptase Inhibitors; Rodent Model; Role; Stress; Structure; Synaptic plasticity; Tenofovir; Therapeutic Effect; Thick; Time; Transcript; Treatment-related toxicity; United States; Up-Regulation; Viremia; Virus; Virus Replication; age related; antiretroviral therapy; behavioral impairment; biological adaptation to stress; cohort; density; emtricitabine; gray matter; in vitro Model; in vivo; indexing; 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.

项目摘要 青少年每年占新艾滋病毒感染的比例不成比例的高度：2018年，30％ 所有新的全球感染均为15-25岁，新美国感染中有21％是 13-24岁2-4岁。但是，我们对新感染和治疗对发展的影响一无所知 在这个关键的时间范围内的大脑。对艾滋病毒+ 18-24岁抗逆转录病毒疗法（ART）的艾滋病毒+ 18-24岁儿童的有限研究 证明多达65％的行为，认知和运动障碍符合艾滋病毒标准 相关的神经认知障碍（Hand）5,6，这一比例高于年龄较大的艾滋病毒+成年人 尽管病毒血症较低，CD4+ T细胞计数较高，并且青少年的感染持续时间较短。 在我们所知的差距是这种功能障碍的机械基础中 系统（CNS）。病毒介导的和/或艺术策略对正常髓鞘和突触的影响 青少年和成年大脑的修剪尚不清楚。有充分记录在功能上至关重要的 白质（WM）和突触可塑性的发展一直持续到二十多岁的人类8。 有趣的是，WM定义了包括髓磷脂病变，髓鞘厚度降低和异常髓鞘 蛋白质表达是HIV+成年人的持续病理发现，其中1，9-11与 病理发现，皮质灰质（GM）的转录组分析和HIV+成人的WM，这都是艺术 天真和艺术治疗，已经揭示了与少突胶质细胞相关的基因表达降低（OL） 分化和髓鞘形成12,13。我们已经显示与HIV相关的神经炎症抑制了OL成熟 通过上调综合应力反应（在HIV+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ARV药物本身会破坏 OL前体细胞在体外的分化和在体内的再生16-18。 ARV药物对 WM病理在临床上不仅在HIV+青少年的护理中都很重要，而且在未感染的青少年中也很重要 使用预防前预防（PREP），两种核侧逆转录酶抑制剂的组合， Emtricerabine（FTC）和替诺福韦毒素富马酸（TDF），以防止HIV感染。我们的初步数据 表明包括FTC和TDF在内的几种ARV药物抑制OL成熟的体外进展 溶酶体功能障碍表明有机胁迫的作用。那我们假设艾滋病毒，艺术和准备 通过有机压力破坏发育性髓鞘，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-的机制 诱导的神经炎症破坏了青少年的OL成熟，2）确定溶酶体功能障碍的作用 在艺术诱导的青少年和成年啮齿动物模型中OL成熟的变化中，以及3） 将目标1和2中的OL成熟和髓鞘措施与磁共振成像措施进行比较 青少年大鼠的WM体积和完整性以及青春期人类的同类群体。