The role of antidepressants in central and peripheral myeloid HIV persistence and inflammation

项目摘要/摘要 这是重新提交的导师研究科学家发展奖(K01)的申请，以支持 史蒂芬妮·马特博士的职业发展，以促进她在 艾滋病毒和神经免疫学研究领域。一个紧张而全面的指导和研究计划 已被开发用于使用高通量技术来评估抗抑郁剂介导的艾滋病毒病毒动力学和 人髓系和共培养模型中的炎症信号。马特博士的培训将得到一家公司的支持 机构对她职业发展的承诺以及由艾滋病毒和艾滋病领域领导人组成的强大指导团队 心理神经免疫学研究领域，每个领域都在发展这两个方面提供战略指导 随着事业的发展，她会向别人求婚并提供指导。拟议的研究计划是 马特博士最近一直在她的导师彼得·加斯基尔博士的实验室进行研究，但其特点是 临床队列中艾滋病毒感染和炎症的检查，生物统计分析，以及神经元 侧写。即使接受抗逆转录病毒治疗，艾滋病毒感染的神经系统并发症(神经性艾滋病毒)仍然很普遍。 (艺术)。抑郁症是这些日益常见的并发症之一，它会使艾滋病毒实质上恶化 疾病的发展。巨噬细胞和小胶质细胞等髓系细胞是HIV的主要靶标 作为病毒宿主并驱动HIV神经发病，但它们的激活也介导了与抑郁症相关的 发炎。艾滋病毒、抑郁症和用于治疗它们的药物之间的炎症联系并不是很好 明白了。然而，艾滋病毒、抑郁症和抗抑郁药作用于受体和转运体，从而改变 神经传递和免疫细胞上的神经递质受体活性可以影响炎症信号 和艾滋病毒感染。这表明，抗抑郁药物对神经递质水平的改变可能会影响大小。 髓系HIV蓄积，加重神经性HIV，影响抑郁症的进展和治疗 抵抗。因此，这一建议的首要假设是，特定的抗抑郁药物可以 激活中枢神经系统和外周髓系细胞，这些细胞对炎症和艾滋病毒起关键作用 坚持不懈。这项提案将使用多方面的方法来检验这一假设，以评估In 体内抗抑郁药物和ART对认知相关髓系细胞病毒动力学和炎症的影响 HIV携带者抑郁患者的功能(目标1)，抗抑郁药物调节离散病毒动态的效果 在感染艾滋病毒、接受抗逆转录病毒药物治疗的IPSC CNS和外周髓系人群中(目标2)，以及抗抑郁药物如何 对HIV感染、ART处理的小胶质细胞和不同细胞共培养中病毒动力学和神经元功能的影响 神经元亚型(目标3)。这些研究将极大地促进我们对细胞 抗抑郁药在HIV神经发病机制中的作用机制。这一机会将提供 全面的培训和坚实的基础，在此基础上建立成功和独立的研究计划 研究神经精神类药物在HIV感染背景下引发炎症的机制。

Project Summary/Abstract This is a resubmission application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Stephanie Matt to facilitate her transition to an independent academic investigator in the HIV and neuroimmunology research fields. An intense and comprehensive mentoring and research plan has been developed to use high-throughput techniques to assess antidepressant-mediated HIV viral dynamics and inflammatory signaling in human myeloid and co-culture models. Dr. Matt’s training will be supported by a firm institutional commitment to her career development and a strong mentoring team of leaders in the HIV and psychoneuroimmunology research fields, each providing strategic guidance in both the development of this proposal and mentoring as her career progresses. The proposed research plan is a natural extension of the recent studies Dr. Matt has been conducting in her mentor Dr. Peter Gaskill’s laboratory but is distinguished by examination of HIV infection and inflammation in clinical cohorts, biostatistical analyses, as well as neuronal profiling. Neurological complications of HIV infection (neuroHIV) remain prevalent even with antiretroviral therapy (ART). Depression is one of these increasingly common complications that can substantively worsen HIV disease progression. Myeloid cells such as macrophages and microglia are primary HIV targets that can serve as viral reservoirs and drive HIV neuropathogenesis, but their activation also mediates depression-associated inflammation. Inflammatory links between HIV, depression, and the drugs used to treat them are not well understood. However, HIV, depression, and antidepressants act on receptors and transporters that alter neurotransmission, and neurotransmitter receptor activity on immune cells can influence inflammatory signaling and HIV infection. This suggests that changes in neurotransmitter levels by antidepressants could affect the size of myeloid HIV reservoirs, exacerbating neuroHIV and influencing the progression of depression and treatment resistance. Thus, the overarching hypothesis of this proposal is that specific antidepressants can activate both CNS and peripheral myeloid cells that critically contribute to inflammation and HIV persistence. This proposal will test this hypothesis using a multifaceted approach to evaluate the effects of in vivo antidepressants and ART on viral dynamics and inflammation in myeloid cells in association with cognitive function in depressed people living with HIV (Aim 1), effects of antidepressants regulating discrete viral dynamics in HIV-infected, ART-treated iPSC CNS and peripheral myeloid populations (Aim 2), and how antidepressants influence viral dynamics and neuronal function in co-cultures of HIV-infected, ART-treated microglia and distinct neuronal subtypes (Aim 3). These studies will significantly advance our understanding of the cellular mechanisms underlying the role of antidepressants in HIV neuropathogenesis. This opportunity will provide comprehensive training and a solid foundation on which to build a successful and independent research program to investigate mechanisms by which neuropsychiatric drugs could drive inflammation in the context of HIV.