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

描述（由申请人提供）：为了响应RFA-DA-12-009，我们的多学科团队建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。这一提议的关键是初步数据， 我们在2009年6月至2011年9月进行的一项试点研究中产生的。我们发现在未感染HIV-1的注射吸毒者中，全身和肠道相关淋巴组织（GALT）的免疫激活水平增加。我们在组织中的发现是新颖的，尽管已经报道了注射吸毒者的免疫激活，但尚未解决相关性和机制的理解。我们广泛的长期目标是使用多方面的方法，包括系统生物学来探索以下问题：1）与活动性IDU相关的血液和组织中免疫激活增加的机制是什么？2)我们能否区分3种可能导致免疫激活水平升高的因素--非无菌注射、阿片类药物的直接影响和丙型肝炎的慢性感染？3)当注射停止时，与活动性IDU相关的增强的免疫激活是否可逆，如果是，可逆性的动力学是什么？4)主动注射如何影响接受联合抗逆转录病毒治疗（cART）的HIV-1感染的注射吸毒者的免疫重建，我们能否定性和定量地描述差异？为了回答这些复杂的问题，我们设计了一种策略，招募了一组HIV- 1未感染和HIV-1感染的活动性注射吸毒者沿着，并与非常仔细匹配的适当对照组一起，我们将从他们那里收集血液、组织和行为数据，包括横截面和纵向数据。HIV-1感染的活性注射者将接受cART治疗， 密切监测病毒学和免疫学应答，并与适当的非注射对照进行比较。我们将分别使用来自血液和组织的细胞亚群上的标记物如CD 38和HLA-DR和Ki 67来测量细胞活化和增殖的水平。还将在患者血浆中测量免疫活化的可溶性标志物的水平。包括药物使用行为在内的行为数据将作为免疫激活和重建的相关因素进行检查。为了响应RFA并反映该项目最具创新性的方面，我们将使用系统生物学方法来解决上述问题。我们将从外周血和组织中挑选特定的细胞群，利用微阵列进行mRNA的转录谱分析。此外，我们还将从体外实验中收集细胞进行转录谱分析，以研究添加和撤销选择的阿片类药物对特定T细胞亚群的影响。在洛克菲勒大学临床和转化科学中心建立的数据分析核心的帮助下，我们将分析转录谱数据，以确定与免疫激活，免疫重建和注射行为标记相关的基因签名和途径。通过研究IDU与HIV-1和HCV感染的交叉点，我们的目标是改善受影响人群和个人的治疗结果。

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.