Correlates and Consequences of Increased Immune Activation in HIV + and - IDUs

HIV 和注射吸毒者免疫激活增加的相关性和后果

基本信息

批准号：
9040131
负责人：
Martin H Markowitz
金额：
$ 92.04万
依托单位：
AARON DIAMOND AIDS RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040131
关键词：
AIDS/HIV problem Address Affect Age Alcohol or Other Drugs use Antiviral Therapy Behavior Behavioral Biological Blood Blood Cells CD4 Positive T Lymphocytes Categories Cell Count Cells Chronic Chronic Hepatitis C Clinical Sciences Collecting Cell Complement Complex Controlled Study Data Data Analyses Disease Drug usage Flow Cytometry Freezing Gene Expression Profile Genomics Global Change Goals Gut associated lymphoid tissue HIV HIV-1 HLA-DR Antigens Hepatitis B Virus Hepatitis C Hepatitis C co-infection Hepatitis C virus Immune Immune response Immune system Immunologics In Vitro Individual Infection Injecting drug user Injection of therapeutic agent Investigation Ligands Longitudinal Studies Maintenance Therapy Measurable Measurement Measures Mediating Messenger RNA Methadone Monitor Morphine Mucous Membrane Opiates Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phenotype Pilot Projects Plasma Plasma Cells Population Population Control Public Health RNA Recording of previous events Recruitment Activity Reporting Research Personnel Risk Behaviors Sampling Sex Behavior Signal Transduction Sorting - Cell Movement Source Systems Biology T-Lymphocyte Subsets Time Tissues Toll-like receptors Translational Research Treatment outcome Universities Viremia Withdrawal adaptive immunity antiretroviral therapy co-infection cohort genetic signature immune activation improved improved outcome in vivo injection drug use innovation interest multidisciplinary new therapeutic target novel peripheral blood reconstitution research study response sex treatment program viral RNA

项目摘要

DESCRIPTION (provided by applicant): In response to RFA-DA-12-009, our multidisciplinary team proposes to study the correlates, consequences, and mechanisms of increased immune activation associated with injection drug use (IDU). Key to this proposal are preliminary data that we generated during a pilot study conducted between June 2009 and September 2011. We discovered increased levels of immune activation systemically and in gut- associated lymphoid tissue (GALT) in HIV-1 uninfected IDUs. Our findings in tissue are novel and though immune activation in IDUs has been reported, an understanding of correlates and mechanism has not been addressed. Our broad term goals are to use a multifaceted approach including systems biology to explore the following questions; 1) What are the mechanisms of increased immune activation in blood and tissue associated with active IDU? 2) Can we separate the effects of 3 possible contributors to increased levels of immune activation- non-sterile injection, direct effects of opiates and chronic infection with Hepatitis C? 3) Is the heightened immune activation associated with active IDU reversible when injection ceases, and if so, what are the dynamics of the reversibility? 4) How does active injection impact immune reconstitution in HIV-1 infected IDUs on combination antiretroviral therapy (cART) and can we characterize differences qualitatively and quantitatively? To answer these complex questions we have devised a strategy to recruit a cohort of HIV- 1-uninfected and -infected active IDUs along with very carefully matched appropriate controls from whom we will collect blood, tissue, and behavioral data both cross-sectionally and longitudinally. HIV-1-infected active injectors will be treated with cART and monitored closely for virologic and immunologic responses and compared to appropriate non-injecting controls. We will measure levels of cellular activation and proliferation using markers such as CD38 and HLA-DR and Ki67 respectively on subsets of cells from blood and tissue. Levels of soluble markers of immune activation will also be measured in patient plasma. Behavioral data including drug use behaviors will be examined as correlates of immune activation and reconstitution. In response to the RFA and reflecting the most innovative aspect of this project, we will use a systems biology approach to address the issues above. We will sort specific cell populations from peripheral blood and tissue for transcriptional profiling of mRNA with the use of microarrays. In addition we will also collect cells from in vitro experiments for transcriptional profiling to study the effects of the addition and withdrawal of select opiates on specific T cell subsets. With the assistance of the Data Analysis Core established by The Rockefeller University Center for Clinical and Translational Science, we will analyze the transcriptional profiling data to identify gene signatures and pathways for correlation with markers of immune activation, immune reconstitution, and injecting behaviors. By studying the intersection of IDU and infection with HIV-1 and HCV, we aim to improve treatment outcomes in affected populations and individuals.

描述（由申请人提供）：响应RFA-DA-12-009，我们的多学科团队提议研究与注射药物使用（IDU）相关的免疫激活增加的相关性，后果和机制。该建议的关键是初步数据我们在2009年6月至2011年9月之间进行的一项试点研究中产生了。我们在HIV-1未感染的IDU中发现了系统地和肠道相关的淋巴组织（GALT）中的免疫激活水平增加。我们在组织中的发现是新颖的，尽管已经报道了IDU中的免疫激活，但对相关和机制的理解尚未得到解决。我们的广泛术语目标是使用包括系统生物学在内的多方面方法来探讨以下问题； 1）与活性IDU相关的血液和组织中免疫激活增加的机制是什么？ 2）我们能否将3个可能的促进因子的影响分开，以增加免疫激活水平 - 非肌电注射水平，直接影响阿片类药物和乙型肝炎的慢性感染？ 3）当注射停止时，与主动IDU可逆相关的免疫激活是否会增加，如果是，可逆性的动力学是什么？ 4）主动注射如何影响HIV-1感染IDU的免疫重建对抗逆转录病毒疗法（CART）的影响，我们可以定性和定量地表征差异吗？为了回答这些复杂的问题，我们制定了一种策略，以招募一系列HIV-1未感染和感染的主动IDU，以及非常仔细的适当对照，我们将从中收集血液，组织和行为数据，均在横截面和纵向上。 HIV-1感染的活性喷油器将用购物车处理，并且密切监测病毒和免疫反应，并与适当的非注射对照进行比较。我们将分别使用CD38和HLA-DR和KI67等标记在血液和组织的子集上分别测量细胞激活和增殖水平。在患者血浆中也将测量免疫激活的可溶性标记水平。包括药物使用行为在内的行为数据将被检查为免疫激活和重建的相关性。为了回应RFA并反映了该项目的最具创新性的方面，我们将使用系统生物学方法来解决上述问题。我们将通过使用微阵列从外周血和组织中对特定的细胞群体进行特定的细胞群体进行转录分析。此外，我们还将从体外实验中收集细胞进行转录分析，以研究添加和戒断选择鸦片对特定T细胞亚群的影响。在洛克菲勒大学临床与转化科学中心建立的数据分析核心的帮助下，我们将分析转录分析数据，以识别与免疫激活，免疫恢复和注射行为的标记相关的基因特征和途径。通过研究IDU与HIV-1和HCV感染的交集，我们旨在改善受影响人群和个人的治疗结果。