Single Cell Analysis of Epigenetic Mechanisms that Regulate HIV-1 CNS Latency and Neuropathogenesis

调节 HIV-1 CNS 潜伏期和神经发病机制的表观遗传机制的单细胞分析

• 批准号: 10748578
• 负责人: CRISTIAN COARFA
• 金额: $ 88.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748578
• 关键词: Antiviral Therapy; Autopsy; Bioinformatics; Blood; Brain; CD4 Positive T Lymphocytes; Cell Line; Cell Nucleus; Cells; Cessation of life; Chromatin; Cognition; Cognitive; Cognitive deficits; Collection; Data; Dementia; Diagnosis; Effectiveness; Epigenetic Process; Gene Expression; Genetic Transcription; Goals; HIV-1; HIV-associated neurocognitive disorder; High Prevalence; Hippocampus; Human; In Vitro; Individual; Infection; Knock-out; Lymphoid Tissue; Messenger RNA; MicroRNAs; Microglia; Minor; Neurocognitive Deficit; Neuropathogenesis; Persons; Prefrontal Cortex; Prior Therapy; Research; Role; Sample Size; Sampling; Site; Specimen; Technology; Therapeutic; Toxic effect; United States; Untranslated RNA; Validation; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; cell type; experimental study; gene network; induced pluripotent stem cell; insight; latent virus activation; motor disorder; neuroAIDS; neurocognitive disorder; neurotropic; novel; novel therapeutic intervention; overexpression; reactivation from latency; single cell analysis; single-cell RNA sequencing; transcriptome sequencing

Current antiretroviral therapies (ART) are successful in suppressing HIV-1 replication in most individuals. However, cessation of ART results in emergence of HIV-1 from a latent viral reservoir, thereby requiring a lifetime ART regime. The best-described HIV-1 reservoir is that of CD4+ T lymphocytes in circulating blood and lymphoid tissues that contain a transcriptionally silent but replication-competent virus. The brain is also an important viral reservoir site, but it is poorly characterized due to the challenges in obtaining specimens for analyses. Despite its effectiveness, multiple toxicities are associated with ART, especially the high prevalence of HIV-associated neurocognitive deficits. The research described in this application will use human autopsy specimens to investigate two key issues regarding HIV-1 infection of the brain: 1) epigenetic mechanisms that regulate active and latent HIV-1 infection in the brain; 2) mechanisms underlying neuropathogenesis and neurocognitive deficits in HIV-1-infected individuals on suppressive ART. Brain specimens from prefrontal cortex and hippocampus from HIV-1 infected individuals treated with ART death will be obtained from the National NeuroAIDS Consortium. Matched HIV-1-negative control specimens will be obtained from the UTHealth Brain Collection. Single cell RNA sequencing technology will be utilized to identify long noncoding RNAs (lncRNAs), mRNAs, and microRNAs (miRNAs) that are dysregulated in HIV-1-infected individuals. Validation experiments will be performed in HIV-1-infected microglia cells to identify dysregulated lncRNAs and miRNAs that contribute to HIV-1 replication, latency, and neuropathogenesis. Completion of the proposed work is likely to identify therapeutic approaches to treat HIV-1 infection of the brain.

目前的抗逆转录病毒疗法（ART）成功地抑制了大多数人的HIV-1复制。 然而，ART的停止导致HIV-1从潜伏的病毒库中出现，从而需要治疗。 终身抗逆转录病毒疗法HIV-1的最佳宿主是循环血液中的CD 4 + T淋巴细胞 以及含有转录沉默但有复制能力的病毒的淋巴组织。大脑也是一个 重要的病毒储库位点，但由于在获得用于 分析。尽管ART有效，但多种毒性仍与ART相关，尤其是高患病率 艾滋病相关的神经认知缺陷本申请中描述的研究将使用人类尸检 研究HIV-1感染大脑的两个关键问题：1）表观遗传机制， 调节大脑中活跃和潜伏的HIV-1感染; 2）神经发病机制， 抑制性抗逆转录病毒治疗对HIV-1感染者神经认知功能的影响 来自用ART治疗死亡的HIV-1感染个体的皮质和海马将从 国家神经艾滋病联盟。匹配的HIV-1阴性质控标本将从 UTHealth脑收集。单细胞RNA测序技术将用于鉴定长非编码区 在HIV-1感染个体中失调的RNA（lncRNA）、mRNA和microRNA（miRNAs）。 验证实验将在HIV-1感染的小胶质细胞中进行，以鉴定失调的lncRNA和 miRNAs参与HIV-1复制、潜伏期和神经发病机制。完成建议 这项工作可能会确定治疗大脑HIV-1感染的治疗方法。