Pharmacogenomics of HIV Therapy

项目总结 美国约有120万人感染艾滋病毒，全球约有3800万人携带艾滋病毒。优先次序 对艾滋病毒的研究包括治愈、减轻相关的炎症和免疫激活、新的疗法、 优化现有管理。此外，艾滋病毒仍然存在有害的个体间变异性。 关于毒性和免疫恢复的治疗反应。努力破译两国之间的关系 艾滋病毒携带者的人类基因组和对治疗干预的反应将有助于推动 在这一领域取得进展，并涉及到补充方法。基因组的公认价值-- 通过考虑多基因风险评分(PRS)扩展了广泛关联研究(GWAS)，该研究考虑了 多种多态基因结合在一起，影响表型的风险，以及综合风险分数 (IRS)，它将PRS与非遗传暴露相结合。它通过转录组范围的进一步扩展 该研究依赖于人体40多个组织中可遗传基因的表达， 从全基因组的基因型数据和全基因组关联研究(Phewas)中推断， 同时询问大量表型的基因型-表型关联。 与这些基于变异和基于基因的方法相辅相成的是强大的湿实验室直接批量和单一 细胞转录组分析(TA)，通过比较基因表达模式来破译潜在的生物学 在不同的实验条件或表型之间。在迄今取得的进展的基础上，我们将应用这些 破译艾滋病毒相关临床和内表型遗传基础的补充方法， 主要是通过分析来自众多不同艾滋病临床试验小组的现有数据和样本 试验和队列。我们将考虑针对炎症、艾滋病毒宿主、病毒复制、 以及更远的地方。这项工作是由提出建议的调查人员奠定的广泛基础来促进的，以创建和 为基于变体、基于基因和基于RNA表达的基因组数据实施高效、强大的系统 生成和数据分析，以及对结果的解释和可视化。我们的最终目标是 通过基于最先进基因组的加速发现来改善艾滋病毒携带者的生活 接近了。

PROJECT SUMMARY Approximately 1.2 million individuals in the United States and 38 million worldwide are living with HIV. Priorities for HIV research include cure, mitigating associated inflammation and immune activation, novel therapeutics, and optimizing current management. In addition, there remains detrimental interindividual variability in HIV treatment responses regarding toxicities and immune recovery. Efforts to decipher relationships between the human genome and responses to therapeutic interventions in people living with HIV will help drive continued progress in the field, and involve complementary methodologies. The well-established value of the genome- wide association study (GWAS) is expanded by considering the polygenic risk score (PRS), which considers numerous polymorphisms that, in combination, affect risk for a phenotype, and by the integrated risk score (IRS), which combines PRS with non-genetic exposures. It is further expanded by the transcriptome-wide association study (TWAS), which relies on heritable gene expression in over 40 tissues throughout the body, inferred from genome-wide genotype data, and by the phenome-wide association study (PheWAS), which simultaneously interrogates genotype-phenotype associations across vast numbers of phenotypes. Complementing these variant-based and gene-based approaches are powerful wet-lab direct bulk and single- cell transcriptome analyses (TA) that decipher underlying biology by comparing patterns of gene expression between different experimental conditions or phenotypes. Building on progress to date, we will apply these complementary approaches to decipher genetic underpinnings of HIV-relevant clinical and endophenotypes, largely through analyses of available data and specimens from numerous different AIDS Clinical Trials Group trials and cohorts. We will consider interventions that target inflammation, the HIV reservoir, viral replication, and beyond. This work is facilitated by extensive groundwork laid by the proposing investigators to create and implement efficient, robust systems for variant-based, gene-based, and RNA expression-based genomic data generation and data analysis, as well as interpretation and visualization of results. Our ultimate goal is to improve the lives of people living with HIV through accelerated discovery based on state-of-the-art genomic approaches.