Gene expression biomarkers of immune recovery in HIV infected patients

HIV感染者免疫恢复的基因表达生物标志物

• 批准号: 8389836
• 负责人: DOUGLAS D RICHMAN
• 金额: $ 32.94万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389836
• 关键词: 3' Untranslated Regions; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Anti-Retroviral Agents; Apoptosis; Biological Markers; Biological Process; CD4 Positive T Lymphocytes; Candidate Disease Gene; Categories; Cell Count; Cells; Cessation of life; Clinical; Disease; Disease Outcome; Drug Targeting; Event; Exhibits; Future; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Goals; HIV; Health; Immune; Immune Targeting; Immune system; In Vitro; Incidence; Individual; Infection; Maps; Messenger RNA; MicroRNAs; Microarray Analysis; Ontology; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacotherapy; Play; Preparation; Protease Inhibitor; RNA; Recovery; Regimen; Regulation; Relative Risks; Reporter; Research; Role; Sampling; Site; Small Interfering RNA; T-Cell Proliferation; Tissue-Specific Gene Expression; Tissues; Transcript; Treatment Protocols; Viral Load result; Virus Replication; base; clinical risk; cohort; cytokine; design; disease diagnosis; in vitro Assay; innovation; mRNA Expression; mRNA Transcript Degradation; non-nucleoside reverse transcriptase inhibitors; novel therapeutics; prevent; programs; public health relevance; response; tool

DESCRIPTION (provided by applicant): Poor immune recovery following highly active antiretroviral treatment (HAART) represents a significant health problem affecting a large proportion (30%) of HIV-infected patients. Despite suppressing HIV replication, patients that are unable to sufficiently increase their CD4+ T cell numbers are at significant risk of clinical progression (AIDS-defining event or death). Currently there is a critical need to define the host genes that contribute to CD4+ T cell recovery in order to identify targets for immune modulating therapies. In addition, it is essential to identify biomarkers that can be used to tailor different HAART-regimens to the individual HIV-infected patient in order to maximize CD4+ T cell recovery and increase the utility of existing therapies. In Aim 1 of this proposal differentially expressed genes between HIV-infected patients (exhibiting complete virological suppression) with a good (DCD4 3200 cells/mm3) versus a poor (DCD4 <200 cells/mm3) outcome after 48 weeks of HAART will be identified using microarrays. We hypothesize that genes contributing to immune recovery will induce CD4+ T cell proliferation and prevent apoptosis and this will be confirmed in vitro by siRNA knockdown and gene over expression analysis. In Aim 2 we will expand upon our preliminary studies that showed gene expression prior to HAART can predict with 100% accuracy which HIV- infected patients progress to good versus poor outcome after 48 weeks of drug treatment. Gene expression classifiers predictive of immune recovery will be constructed exclusively for HIV-infected patients treated with a protease inhibitor (PI)-based HAART regimen, and then for patients treated with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using an innovative approach we will then use the PI-based gene expression classifier to determine if any of the poor outcome patients that were treated with an NNRTI- based regimen were predicted as having a good outcome under a PI-based regimen, and vice versa. In this way we will identify the total number of patients that were placed on the wrong regimen with respect to CD4+ T cell recovery. In the future we will be able to tailor different HAART regimens to the individual patient to increase the extent of immune recovery. In Aim 3 the role of microRNAs (miRNAs) in immune recovery will be investigated. We hypothesize that miRNA degradation of mRNA targets represents one mechanism contributing to the differential gene expression between good and poor outcome groups (Aim 3A), and that a combination of miRNA expression with gene expression will result in more accurate classifiers (Aim 3B). When these studies are complete we will have identified the host genes (i.e. cytokines) that cause immune recovery in HIV-infected patients treated with HAART and may be formulated into immune modulating therapies in the future. We will also have developed gene expression biomarkers capable of guiding the treatment options for HIV-infected patients in order to maximize increases in CD4+ T cell numbers.

描述（由申请人提供）：高效抗逆转录病毒治疗（HAART）后免疫恢复不良是影响大部分（30%）HIV感染患者的重大健康问题。尽管抑制了HIV复制，但不能充分增加其CD 4 + T细胞数量的患者仍存在临床进展（AIDS定义事件或死亡）的重大风险。目前，迫切需要确定有助于CD 4 + T细胞恢复的宿主基因，以确定免疫调节疗法的靶点。此外，重要的是要确定生物标志物，可用于定制不同的HAART方案，以最大限度地提高CD 4 + T细胞的恢复和增加现有疗法的效用。 在该建议的目的1中，将使用微阵列鉴定在HAART 48周后具有良好（DCD 4 3200个细胞/mm 3）与较差（DCD 4 <200个细胞/mm 3）结果的HIV感染患者（表现出完全病毒学抑制）之间差异表达的基因。我们假设有助于免疫恢复的基因将诱导CD 4 + T细胞增殖并防止凋亡，这将通过siRNA敲低和基因过表达分析在体外证实。在目标2中，我们将扩展我们的初步研究，这些研究表明HAART前的基因表达可以100%准确地预测哪些HIV感染患者在48周的药物治疗后进展为良好或不良结局。预测免疫恢复的基因表达分类器将专门针对用基于蛋白酶抑制剂（PI）的HAART方案治疗的HIV感染患者构建，然后针对用基于非核苷逆转录酶抑制剂（NNRTI）的方案治疗的患者构建。使用一种创新的方法，我们将使用基于PI的基因表达分类器来确定用基于NNRTI的方案治疗的任何不良结果患者是否被预测为在基于PI的方案下具有良好的结果，反之亦然。通过这种方式，我们将确定在CD 4 + T细胞恢复方面接受错误方案的患者总数。在未来，我们将能够为个体患者量身定制不同的HAART方案，以增加免疫恢复的程度。在目标3中，将研究microRNA（miRNAs）在免疫恢复中的作用。我们假设，mRNA靶点的miRNA降解代表了导致良好和不良结局组之间差异基因表达的一种机制（目的3A），并且miRNA表达与基因表达的组合将产生更准确的分类器（目的3B）。 当这些研究完成时，我们将确定宿主基因（即细胞因子），这些基因在接受HAART治疗的HIV感染患者中引起免疫恢复，并且将来可能被配制成免疫调节疗法。我们还将开发出能够指导HIV感染患者治疗选择的基因表达生物标志物，以最大限度地增加CD 4 + T细胞数量。