Cocaine enhances HIV replication by inducing transcriptionally active chromatin s

可卡因通过诱导转录活性染色质增强 HIV 复制

• 批准号: 8329932
• 负责人: Mudit Tyagi
• 金额: $ 19.81万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329932
• 关键词: AIDS neuropathy; Acetylation; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Biological Assay; Brain; Cells; Chromatin; Chromatin Structure; Chronic; Cocaine; Cocaine Abuse; Complex; Critical Pathways; Cytokine Signaling; Deterioration; Disease Outcome; Doxycycline; Drug Targeting; Drug abuse; Drug usage; Ensure; Enzymes; Epigenetic Process; Event; Excision; Feline Immunodeficiency Virus; Gene Expression; Generations; Genes; Genetic Transcription; Grant; HIV; HIV Long Terminal Repeat; HIV-1; Highly Active Antiretroviral Therapy; Histone Acetylation; Histone H3; Histone H4; Histones; Illicit Drugs; Immune system; Individual; Injection of therapeutic agent; Intervention; Knowledge; Laboratories; Lead; Lentivirus Vector; Microglia; Modification; Molecular; Myeloid Cells; Nervous system structure; Neuraxis; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmacologic Substance; Physiological; Process; Proviruses; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Testing; United States; Up-Regulation; Viral; Viral Proteins; Virus Diseases; Virus Replication; Work; base; brain cell; cell type; chemokine; chromatin modification; cofactor; drug addict; drug of abuse; experience; histone acetyltransferase; improved; macrophage; novel therapeutics; overexpression; public health relevance; research study; small hairpin RNA; transmission process; verdin photosensitizer

DESCRIPTION (provided by applicant): Injection and non-injection drug use and abuse remain significant cofactors for HIV infection and transmission. The drugs of abuse such as cocaine has also been implicated in HIV-1-associated pathogenesis e.g. HAD, HAND. It has become clear that drugs of abuse, including cocaine can modify both cellular epigenetics and signaling pathways, which ultimately modulate the expression of several cellular genes. Therefore, it would not be surprising if the gene expression of integrated HIV proviruses are also influenced with this type of stimuli. Although, HIV gene expression by cocaine until now is mainly attributed to up regulation of several chemokines, cytokines, signaling pathways and some of viral proteins (e.g. Tat and Env), however, the molecular mechanism such as epigenetic changes by drugs of abuse could explain better the continuous induction of several genes even after removal of drug of abuse, which is normally the case. In order to develop better understanding of the complex interplay between drugs of abuse and HIV replication, it is important to investigate the impact of drugs of abuse on HIV gene expression especially in brain cells, as brain is the target organ for both drugs of abuse and HIV. Cocaine is one of the most widely abused drugs in the United States, which both impair the normal functioning of brain cells and also activate HIV gene expression in central nervous system (CNS). As a result, HIV-infected individuals who abuse cocaine experience more severe and rapid onset of NeuroAIDS than non-abusing individuals. In this grant we will study the molecular mechanisms involved in the regulation of HIV gene expression and replication by cocaine in two primary macrophage cells, microglial (from brain) and peripheral macrophage (MDMs from PBMCs). Cocaine is known to modulate expression of several cellular genes via inducing selective chromatin modifications by regulating specific set of enzymes. We will investigate how gene expression of integrated HIV provirus is affected by cocaine induced selective core histones acetylations in primary macrophage cells. These modifications ultimately contribute to more rapid deterioration of immune and nervous system, which is quite prevalent in drug addict HIV patients. Broader Impact: This work is expected to lead towards the discovery of new epigenetic pathways, which could direct towards the new therapeutic strategies to address several adverse disease outcomes due to aberrant proviral gene expression and replication in drug addict HIV patients.

描述（由申请人提供）：注射和非注射药物的使用和滥用仍然是 HIV 感染和传播的重要辅助因素。可卡因等滥用药物也与 HIV-1 相关的发病机制有关。有，手。很明显，包括可卡因在内的滥用药物可以改变细胞表观遗传学和信号通路，最终调节多个细胞基因的表达。因此，如果整合的 HIV 原病毒的基因表达也受到此类刺激的影响，也就不足为奇了。尽管到目前为止，可卡因引起的HIV基因表达主要归因于几种趋化因子、细胞因子、信号通路和一些病毒蛋白（例如Tat和Env）的上调，然而，滥用药物引起的表观遗传变化等分子机制可以更好地解释即使在消除滥用药物后仍会持续诱导一些基因，这通常是这种情况。为了更好地了解滥用药物和 HIV 复制之间复杂的相互作用，研究滥用药物对 HIV 基因表达（尤其是脑细胞）的影响非常重要，因为大脑是滥用药物和 HIV 的靶器官。可卡因是美国滥用最广泛的药物之一，它不仅会损害脑细胞的正常功能，还会激活中枢神经系统 (CNS) 中的 HIV 基因表达。因此，滥用可卡因的艾滋病毒感染者比不滥用可卡因的人会经历更严重和更快的神经艾滋病发作。 在这笔资助中，我们将研究可卡因在两种初级巨噬细胞（小胶质细胞（来自大脑）和外周巨噬细胞（来自 PBMC 的 MDM））中调节 HIV 基因表达和复制的分子机制。已知可卡因通过调节特定的酶组诱导选择性染色质修饰来调节多种细胞基因的表达。我们将研究可卡因诱导的原代巨噬细胞中选择性核心组蛋白乙酰化如何影响整合的 HIV 原病毒的基因表达。这些修饰最终导致免疫和神经系统更快恶化，这在吸毒成瘾的艾滋病毒患者中相当普遍。更广泛的影响：这项工作预计将导致新的表观遗传途径的发现，这可能会指导新的治疗策略，以解决由于吸毒成瘾的艾滋病毒患者中前病毒基因表达和复制异常而导致的几种不良疾病结果。