Effects of HIV and ART on myelination in the adolescent

项目摘要 青少年在每年新感染艾滋病毒的人数中所占比例过高：2018年， 所有新的全球感染者都在15-25岁之间，美国所有新感染者中有21%在15 - 25岁之间。 13-24岁2-4岁。然而，我们对新感染和治疗对发展中国家的影响知之甚少， 在这个关键的时间段。对接受和不接受抗逆转录病毒治疗的18-24岁艾滋病毒阳性者的研究有限 表明高达65%的人出现符合艾滋病毒标准的行为、认知和运动障碍 相关的神经认知障碍（HAND）5，6，比例高于老年HIV+成人同行 尽管青少年中病毒血症较低，CD 4 + T细胞计数较高，感染持续时间较短。一个主要 我们知识上的差距是发育中的中枢神经系统功能障碍的机械基础。 系统（CNS）。病毒介导的和/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中的修剪是未知的。有充分的证据表明， 白色物质（WM）和突触可塑性的发育持续到人类20多岁。 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HIV+成人HAND 1，9 -11的持续病理学发现之一。 病理学发现，皮质灰质（GM）和来自HIV+成人的WM的转录组分析，两种ART- 幼稚和ART治疗，显示与少突胶质细胞（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相关的神经炎症抑制OL成熟 通过上调整合的应激反应（一种在HIV+的CNS中表现出失调的途径）， 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 体外OL前体细胞的分化和体内髓鞘再生16-18。抗逆转录病毒药物对 WM病理学不仅在HIV+青少年的护理中具有临床重要性，而且在未感染的青少年中也具有临床重要性 使用暴露前预防（PrEP），一种两种核苷逆转录酶抑制剂的组合， 恩曲他滨（FTC）和富马酸替诺福韦二异丙酯（TDF），以预防HIV感染。我们的初步数据 表明几种抗逆转录病毒药物，包括FTC和TDF，通过以下途径抑制体外OL成熟的进展： 溶酶体功能障碍提示细胞器应激的作用。因此，我们假设艾滋病毒，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CNS缺陷 在青少年和年轻人中观察到。我们建议：1）确定艾滋病毒- 诱导的神经炎症破坏青少年OL成熟，2）确定溶酶体功能障碍的作用 在青春期和青年期啮齿动物模型中ART诱导的OL成熟变化，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 WM体积和完整性在青春期大鼠和一个预先存在的青少年人类队列。

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.