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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：
10626056
负责人：
MARCUS KAUL
金额：
$ 61.26万
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/10626056
关键词：
Acquired Immunodeficiency Syndrome Affect Age Anti-Retroviral 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 Engraftment Gene Expression Gene Expression Regulation 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 Macrophage Methamphetamine Microglia Mitogen-Activated Protein Kinases Molecular Monitor Nucleotides Pathologic Patients Peripheral Peripheral Blood Lymphocyte Phagocytosis Inhibition Pharmaceutical Preparations Physiological Proliferating Protein Kinase Public Health RANTES RNA Recrudescences Recurrence Regulator Genes Reporting Research Risk Risk Behaviors Role Signal Transduction Stress T-Cell Activation T-Lymphocyte Testing Trans-Activators Transcription Coactivator 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 methamphetamine abuse methamphetamine effect methamphetamine exposure methamphetamine use monocyte mouse model p38 Mitogen Activated Protein Kinase permissiveness prevent promoter protein expression psychostimulant receptor stem cell engraftment 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感染经常与滥用精神兴奋剂有关毒品，如甲基苯丙胺（METH）。病毒和精神兴奋剂的相互作用，特别是病毒的持久性，是知之甚少，将在这里研究使用体外和体内的方法。我们最近观察到，阻断p38 MAPK和敲低或缺失lncRNA linc 02574 -201可以抑制HIV-1复制。因此，在本申请中，我们提出研究一种或多种机制， METH明显促进HIV-1感染，p38 MAPK和lncRNA linc 02574- 201.本研究的目的有三：1）研究甲基苯丙胺（METH）对HIV-1的促发作用外周血淋巴细胞和单核细胞/巨噬细胞感染。这一目标将检验以下假设：甲基苯丙胺暴露通过促进HIV-1的表达，以浓度和时间依赖的方式影响HIV-1感染。 p38 MAPK活性和lnRNA linc 02574 -201的表达。2)为了研究甲基苯丙胺如何干扰病毒联合抗逆转录病毒治疗（cART）。这一目标将调查如何METH暴露影响 cART的病毒抑制和一旦停止ARV治疗病毒复发。这一目标还将评估p38 MAPK的抑制或敲低是否可以阻止cART后病毒复制的恢复，类似于 lncRNA linc 02574 -201的敲低。3)在人源化CD 34 + HSC移植的NSG小鼠中评估如果METH增加了病毒库，并在cART中断期间促进HIV复发，则模型。这目的是研究METH如何影响HIV-1感染、cART的病毒抑制和在HIV允许的体内模型中，cART中断，CD 34 + HSC（造血干细胞）-移植 NSG小鼠模型。实验将在体外用分离的人外周血细胞进行，细胞系，并在体内在具有CD 34+细胞来源的造血系统的人源化小鼠中提供HIV 允许的人外周CD 4 + T淋巴细胞和巨噬细胞（MΦ）。三个具体目标将确定在存在和不存在METH的情况下，使用RNA标记HIV-1感染的CD 4 + T细胞和MΦ的RNA特征。测序，并将测试拟议的机制，包括增加活动的压力相关的p38 MAPK 和lncRNA linc 02574 -201的上调。这些目标还将监测已知的支持HIV-1感染的因素，如IRF 7，并将测试METH暴露下调ISG子集的前提，包括抗病毒因子，如CCL 5、Mx 1/2、IFITM 2/3和IRF 1和IRF 3。