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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：
10197871
负责人：
MARCUS KAUL
金额：
$ 64.34万
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/10197871
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.

项目概要人类免疫缺陷病毒 (HIV)-1 感染常常与滥用精神兴奋剂有关药物，例如甲基苯丙胺 (METH)。病毒和精神兴奋剂的相互作用，特别是在以下方面对于病毒持久性的影响，人们知之甚少，这里将使用体外和体内方法进行研究。我们最近观察到，阻断 p38 MAPK 和敲低或删除 lncRNA linc02574-201 可以抑制HIV-1复制。因此，我们建议在本申请中研究以下机制： METH 明显促进 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：接触冰毒会促进 HIV-1 感染，并以浓度和时间依赖性方式影响 HIV-1 感染。 p38 MAPK 的活性和 lnRNA linc02574-201 的表达。 2) 研究冰毒如何干扰病毒通过联合抗逆转录病毒治疗（cART）进行抑制。该目标将调查冰毒暴露如何影响 cART 对病毒的抑制以及抗逆转录病毒治疗停止后病毒的复发。这一目标也将评估 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 lncRNA linc02574-201 的敲低。 3) 在人源化 CD34+ HSC 移植 NSG 小鼠中进行评估如果 METH 在 cART 中断期间增加病毒库并促进 HIV 复发，则建立模型。这目标将研究冰毒如何影响 HIV-1 感染、cART 的病毒抑制以及病毒复发在 HIV 允许的体内模型中中断 cART，即植入 CD34+ HSC（造血干细胞） 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，以及具有提供 HIV 的 CD34+ 细胞衍生造血系统的人源化小鼠体内允许的人外周 CD4+ T 淋巴细胞和巨噬细胞 (MΦ)。所有三个具体目标将定义使用 RNA- 在存在和不存在 METH 的情况下，HIV-1 感染的 CD4+ T 细胞和 MΦ 的 RNA 特征测序并将测试所提出的机制，包括应激相关 p38 MAPK 活性的增加和 lncRNA linc02574-201 的上调。这些目标还将监测已知支持 HIV-1 感染的因素，例如 IRF7，并将测试 METH 暴露下调 ISG 子集的前提，其中包括抗病毒因子，例如 CCL5、Mx1/2、IFITM2/3 以及 IRF1 和 -3。