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.

当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。 但是，停止艺术结果导致潜在病毒储存中的HIV-1出现，从而需要 终身艺术制度。最佳描述的HIV-1储层是循环血液中的CD4+ T淋巴细胞 和淋巴组织，其中包含转录静音但具有复制能力的病毒。大脑也是 重要的病毒储层站点，但是由于获得标本的挑战，其特征很差 分析。尽管具有有效性，但多种毒性与艺术有关，尤其是高流行率 与HIV相关的神经认知缺陷。本应用程序中描述的研究将使用人类尸检 标本要研究有关大脑HIV-1感染的两个关键问题：1）表观遗传机制 调节大脑中的活跃和潜在的HIV-1感染； 2）神经病发生和 HIV-1感染者的神经认知缺陷。前额叶的大脑标本 来自ART死亡治疗的HIV-1感染个体的皮质和海马将从 国家神经辅助财团。匹配的HIV-1阴性控制标本将从 Uthealth Brain收集。单细胞RNA测序技术将用于识别长期不编码 在HIV-1感染的个体中失调的RNA（LNCRNA），mRNA和microRNA（miRNA）。 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 有助于HIV-1复制，潜伏期和神经病的miRNA。拟议的完成 工作可能会确定治疗大脑HIV-1感染的治疗方法。