Defining the impact of injection drug use on antiretroviral therapy and HIV treatment outcomes: an (epi)genomic approach

尽管联合抗逆转录病毒疗法(CART)在注射毒品(PWID)感染者中的吸收 艾滋病毒在过去十年中急剧增加，健康状况不佳，包括与艾滋病无关的 CART上感染艾滋病毒的PWID的共病和死亡率仍然是一个重大的公共卫生问题。一个至关重要的 知识鸿沟是对注射吸毒(IDU)如何影响艾滋病毒进程的了解不足 疾病。IDU和不遵守CART影响的基因调控的差异可能会影响 可能导致不良结果的这些治疗的药代动力学和药效学。因此，有 迫切需要确定PWID的基因组特征并将PWID相关的基因组信号与HIV联系起来 在CART暴露的情况下的结果(即血浆中的水平)。我们的总体假设是PWID 增加DNA甲基化(DNaM)和转录组变异，影响健康结果，并可能 部分原因是购物车暴露的可变性。这一假设是建立在我们之前的发现基础上的，即 注射用药显著改变了HIV感染者的血液DNA甲基组。此外，dNaM 与注射吸毒者相关的特征区分出越来越少的HIV疾病脆弱性。为了验证这一假设，我们的 方法将首先执行表观基因组范围的dNaM关联分析和转录组范围的关联 HIV感染者与非HIV感染者接受CART治疗的对比分析 独立的队列。其次，我们将测试PWID相关的差异甲基化之间的关系 血浆和血浆中CART变异的位置(DMP)或区域(DMR)和差异基因表达(DGE) 以及它们与艾滋病毒脆弱性和死亡率的关系。最后，我们提出了整合遗传变异(单一的 核苷酸多态[SNP])、dNaM和基因表达因HIV感染的PWID/非PWID而不同 状态。我们的目标是在HIV感染的PWID和非PWID之间识别DMP或DMR和DGE 并应用表观遗传和转录签名作为生物标记物来预测艾滋病毒的脆弱性和 死亡率。 该申请提出了第一个遗传变异的综合药物基因组学方法，表观基因组和 在CART的背景下，HIV感染PWID的转录相关。我们希望确认PWID- 可以预测HIV CART治疗结果的相关基因。由此产生的预测模型 该项目可以为艾滋病毒结果的生物标记物识别提供信息。这项提议是迈向 对HIV感染的PWID患者的药物基因组学和药物表观基因组学的理解。结果会填满 对注射吸毒者生物学基础的认识差距对艾滋病毒结局的影响并提供证据以确定优先次序 未来研究它们在艾滋病毒进展中的作用的基因。

Although uptake of combination antiretroviral therapy (cART) in people who inject drugs (PWID) infected with HIV has increased dramatically in the past decade, poor health outcomes including non-AIDS-related comorbidity and mortality in HIV-infected PWID on cART remains a significant public health problem. A crucial knowledge gap is a lack of the understanding about how injection drug use (IDU) impacts the course of HIV disease. Differences in gene regulation affected by IDU and non-adherence to cART are likely to affect the pharmacokinetics and pharmacodynamics of these treatments that may result in poor outcomes. Thus, there is an urgent need to identify genomic signatures for PWID and to link PWID-associated genomic signals to HIV outcomes in the context of cART exposure (i.e., levels in plasma). Our overall hypothesis is that PWID accrue DNA methylation (DNAm) and transcriptome variations that impact on health outcomes, and which may be explained in part by variability in cART exposure. This hypothesis is built on our previous findings showing that IDU significantly altered the blood DNA methylome in HIV-infected individuals. Furthermore, DNAm signatures associated with IDU differentiated less and greater HIV disease frailty. To test this hypothesis, our approach will first perform epigenome-wide DNAm association analysis and transcriptome-wide association analysis in HIV-infected PWID as compared to HIV-infected non-PWID who are treated with cART in two independent cohorts. Second, we will test the relationship between PWID-associated differentially methylated positions (DMP) or regions (DMR) and differential gene expression (DGE) on cART variability in plasma and also their relationships with HIV frailty and mortality. Last, we propose to integrate genetic variation (single nucleotide polymorphism [SNP]), DNAm, and gene expression that differs by HIV-infected PWID/non-PWID status. Our goal is to identify DMP or DMR and DGE between HIV-infected PWID and non-PWID in the context of cART and to apply epigenetic and transcriptomic signatures as biomarkers to predict HIV frailty and mortality. The application proposes the first integrative pharmacogenomic approach of genetic variants, epigenomic and transcriptomic associations for HIV-infected PWID in the context of cART. We expect to identify PWID- associated genes that can predict HIV cART treatment outcomes. The predictive model resulting from this project can inform biomarker identification for HIV outcomes. The proposal is the first step towards the understanding of pharmacogenomics and pharamcoepigenomics in PWID with HIV infection. The results will fill the knowledge gap of the biological basis of IDU effects on HIV outcomes and provide evidence to prioritize genes for future research of their functions in HIV progression.