Methamphetamine Effect on HIV Persistence

甲基苯丙胺对艾滋病毒持续存在的影响

基本信息

批准号：
10080506
负责人：
MARCUS KAUL
金额：
$ 64.69万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10080506
关键词：
Acquired Immunodeficiency Syndrome Affect Age Anti-Retroviral Agents Antiviral Agents Blood Blood Cells CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Line Cell physiology Cells Collaborations Contracts DNA Data Dendritic Cells Development Disease Exposure to Gene Expression Regulation Genetic Transcription Glycoproteins HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Hematopoietic System Hematopoietic stem cells Human IRF1 gene Immune In Vitro Individual Infection Interruption Lead Link Methamphetamine Microglia Mitogen-Activated Protein Kinases Molecular Monitor Nucleotides Pathologic Peripheral Peripheral Blood Lymphocyte Phagocytosis Pharmaceutical Preparations Physiological Protein Kinase Public Health RANTES RNA Recrudescences Recurrence Regulator Genes Reporting Research Risk Role Signal Transduction Stress T-Cell Activation T-Lymphocyte Testing Trans-Activators Untranslated RNA Up-Regulation Viral Viral Load result Viral reservoir Virus Virus Replication Withholding Treatment antigen processing antiretroviral therapy cellular targeting drug of abuse epigenetic regulation exhaustion experimental study genetic regulatory protein humanized mouse improved in vivo in vivo Model infection risk knock-down link protein macrophage methamphetamine abuse methamphetamine effect methamphetamine exposure methamphetamine use monocyte mouse model p38 Mitogen Activated Protein Kinase prevent protein expression psychostimulant receptor stimulant abuse transcriptome sequencing

项目摘要

PROJECT SUMMARY Infection with Human Immunodeficiency virus (HIV)-1 is frequently associated with abuse of psychostimulant drugs, such as methamphetamine (METH). The interaction of virus and psychostimulant, in particular with regard to viral persistence, is poorly understood and will be studied here using in vitro and in vivo approaches. We recently observed that blockade of p38 MAPK and knockdown or deletion of the lncRNA linc02574-201 can inhibit HIV-1 replication. Therefore, we propose in this application to investigate the mechanism(s) by which METH apparently promotes HIV-1 infection and the potential contributions of p38 MAPK and lncRNA linc02574- 201. Three Specific Aims are proposed: 1) To investigate how methamphetamine (METH) increases HIV-1 infection of peripheral blood lymphocytes and monocytes/macrophages. This aim will test the hypothesis that METH exposure affects HIV-1 infection in a concentration- and timing-dependent fashion by promoting the activity of p38 MAPK and expression of lnRNA linc02574-201. 2) To study how METH interferes with viral suppression by combined antiretroviral therapy (cART). This aim will investigate how METH exposure affects viral suppression by cART and the recrudescence of the virus once ARV treatment ceases. This aims will also assess if inhibition or knockdown of p38 MAPK can prevent the resumption of viral replication after cART, similar to the knockdown of lncRNA linc02574-201. 3) To assess in a humanized CD34+ HSC-engrafted NSG mouse model if METH increases the viral reservoir and facilitates the recurrence of HIV during interruption of cART. This aim will study how METH affects HIV-1 infection, viral suppression by cART and viral recrudescence upon interruption of cART in an HIV permissive in vivo model, the CD34+ HSC (hematopoietic stem cell)-engrafted NSG mouse model. The experiments will be performed in vitro with isolated human peripheral blood cells and cell lines, and in vivo in humanized mice with a CD34+ cell-derived hematopoietic system that provides HIV permissive human peripheral CD4+ T-lymphocytes and macrophages (MΦ). All three Specific Aims will define RNA signatures of HIV-1 infected CD4+ T-cells and MΦ in the presence and absence of METH using RNA- sequencing and will test the proposed mechanism, including increased activity of the stress-related p38 MAPK and up-regulation of lncRNA linc02574-201. The aims will also monitor factors known to support HIV-1 infection, such as IRF7, and will test the premise that METH exposure down-regulates a subset of ISGs that include antiviral factors, such as CCL5, Mx1/2, IFITM2/3 and IRF1 and -3.

项目摘要人类免疫缺陷病毒（HIV）-1的感染经常与滥用精神刺激有关药物，例如甲基苯丙胺（甲基苯丙胺）。病毒与精神刺激剂的相互作用，特别是与为了病毒的持久性，人们对使用体外和体内方法的理解很少。我们最近观察到p38 mapk的封锁和lncrna linc02574-201的敲低或删除抑制HIV-1复制。因此，我们建议在本申请中调查该机制 Meth显然促进了HIV-1感染以及p38 MAPK和LNCRNA LINC02574-的潜在贡献 201。提出了三个具体目标：1）研究甲基苯丙胺（METH）如何增加HIV-1 外周血淋巴细胞和单核细胞/巨噬细胞的感染。这个目标将检验以下假设甲基甲基暴露通过促进浓度依赖于浓度和时机的方式影响HIV-1感染 p38 MAPK的活性和LNRNA linc02574-201的表达。 2）研究甲基如何干扰病毒抗逆转录病毒疗法（CART）抑制。这个目标将调查甲基甲基甲基暴露如何影响一旦ARV治疗停止，CART抑制病毒和病毒的重新抑制作用。这个目标也将评估p38 MAPK的抑制或敲低是否可以防止卡车后的病毒复制恢复，类似 lncrna linc02574-201的敲低。 3）在人源化的CD34+ HSC促进NSG小鼠中评估如果Meth增加了病毒储量，并促进CART中断期间的HIV复发。这 AIM将研究METH如何影响HIV-1感染，通过CART抑制病毒和病毒复发的方式。在HIV允许体内模型中，CD34+ HSC（造血干细胞）中断推车的中断 NSG鼠标模型。实验将在体外用分离的人类外周血细胞和细胞系，在人源化小鼠中具有CD34+细胞衍生的造血系统的体内，可提供HIV 允许的人外围CD4+ T淋巴细胞和巨噬细胞（Mφ）。这三个特定目标都将定义 HIV-1感染CD4+ T细胞的RNA特征和Mφ在使用RNA的存在和不存在Met的情况下测序并将测试提出的机制，包括增加与应力相关p38 MAPK的活性 LNCRNA LINC02574-201的上调。目的还将监测已知支持HIV-1感染的因素，例如irf7，并将测试甲基甲基甲基苯暴露量下调的前提抗病毒因子，例如CCL5，MX1/2，IFITM2/3和IRF1和-3。