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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：高度活跃的抗逆转录病毒治疗后的免疫恢复差（HAART）代表了影响大部分（30％）的HIV感染患者的重大健康问题。尽管抑制了HIV复制，但无法充分增加其CD4+ T细胞数量的患者有临床进展的很大风险（定义艾滋病事件或死亡）。当前，至关重要的是定义有助于CD4+ T细胞回收的宿主基因，以识别免疫调节疗法的靶标。此外，必须识别可用于为单个HIV感染的患者量身定制不同HAART调制的生物标志物，以最大程度地提高CD4+ T细胞恢复并增加现有疗法的效用。在本提案的目标1中，在HAART 48周后，HAART结束后的较差（DCD4 <200细胞/mm3）与较差（DCD4 <200细胞/mm3）相比，HIV感染患者（表现出完全的病毒学抑制）之间的差异表达基因。我们假设有助于免疫恢复的基因将诱导CD4+ T细胞增殖并预防凋亡，这将通过siRNA敲低和基因在表达分析中在体外得到证实。在AIM 2中，我们将扩展我们的初步研究，该研究表明，HAART之前的基因表达可以通过100％的精度预测，而感染HIV感染的患者在药物治疗48周后会发展为良好与良好结果。预测免疫恢复的基因表达分类器将专门针对接受蛋白酶抑制剂（PI）基于HAART治疗的HIV感染患者，然后针对接受非核苷逆转录酶抑制剂（NNRTI）基于非核苷逆转录酶治疗的患者。然后，我们将使用创新的方法使用基于PI的基因表达分类器来确定是否有任何基于NNRTI的治疗方案治疗的较差的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，我们将在CD4+ T细胞回收方面确定放置在错误方案上的患者总数。将来，我们将能够为个体患者量身定制不同的HAART方案，以增加免疫康复的程度。在AIM 3中，将研究microRNA（miRNA）在免疫恢复中的作用。我们假设mRNA靶标的miRNA降解代表了一种有助于良好和差的结果组之间差异基因表达（AIM 3A）的机制（AIM 3A），并且将miRNA表达与基因表达的组合将导致更准确的分类器（AIM 3B）。完成这些研究完成后，我们将确定宿主基因（即细胞因子）在接受HAART治疗的HIV感染患者中引起免疫恢复的宿主基因，并可能在将来将其配合为免疫调节疗法。我们还将开发出能够指导感染HIV患者的治疗选择的基因表达生物标志物，以最大程度地增加CD4+ T细胞数量。