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: 7840606
• 负责人: CHRISTOPHER H WOELK
• 金额: $ 35.4万
• 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/7840606
• 关键词: 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 Delivery Systems; Event; Exhibits; Future; Gene Expression; 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; Risk; Role; Sampling; Site; Small Interfering RNA; T-Cell Proliferation; Tissue-Specific Gene Expression; Tissues; Transcript; Treatment Protocols; Untranslated Regions; Viral Load result; Virus Replication; base; 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. PUBLIC HEALTH RELEVANCE: Many HIV-infected patients fail to recover their immune system when placed on drug therapy. This research will identify patient genes that contribute to immune recovery and represent new targets for drugs that can be used to increase immune recovery. This proposal will also identify which drugs an HIV-infected patient should be treated with in order to maximize the extent of their immune recovery.

描述(由申请人提供)：高效抗逆转录病毒治疗(HAART)后免疫恢复差是一个严重的健康问题，影响到很大比例(30%)的艾滋病毒感染患者。尽管抑制了艾滋病毒的复制，但不能充分增加其CD4+T细胞数量的患者面临着临床进展(艾滋病定义事件或死亡)的重大风险。目前，迫切需要确定促进CD4+T细胞恢复的宿主基因，以便确定免疫调节治疗的靶点。此外，为了最大限度地恢复CD4+T细胞并提高现有治疗方法的有效性，必须确定可用于为个体HIV感染患者量身定制不同HAART方案的生物标志物。在这项建议的目标1中，将使用微阵列识别HAART 48周后结果良好(DCD43200细胞/mm3)和较差(DCD4200细胞/mm3)的艾滋病毒感染患者(显示出完全的病毒学抑制)之间的差异表达基因。我们假设促进免疫恢复的基因将诱导CD4+T细胞增殖并防止细胞凋亡，这一假设将通过siRNA敲除和基因过度表达分析在体外得到证实。在目标2中，我们将扩展我们的初步研究，表明HAART之前的基因表达可以100%准确地预测HIV感染患者在药物治疗48周后进展为良好还是不良结果。预测免疫恢复的基因表达分类器将专门针对接受基于蛋白酶抑制剂(PI)的HAART方案治疗的HIV感染患者，然后针对接受非核苷逆转录酶抑制剂(NNRTI)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是否有任何接受基于NNRTI的方案治疗的不良结果患者在基于PI的方案下被预测为具有良好的结果，反之亦然。通过这种方式，我们将确定在恢复CD4+T细胞方面被安排在错误方案中的患者总数。在未来，我们将能够针对不同的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microRNAs(MiRNAs)在免疫恢复中的作用。我们假设，mRNA靶标的miRNA降解是导致良好和不良结果组之间基因表达差异的一种机制(目标3A)，并且miRNA表达和基因表达的组合将产生更准确的分类器(目标3B)。当这些研究完成后，我们将确定在接受HAART治疗的HIV感染患者中导致免疫恢复的宿主基因(即细胞因子)，并可能在未来被配方为免疫调节疗法。我们还将开发基因表达生物标记物，能够指导艾滋病毒感染患者的治疗选择，以便最大限度地增加CD4+T细胞数量。 公共卫生相关性：许多艾滋病毒感染患者在接受药物治疗时未能恢复他们的免疫系统。这项研究将确定有助于免疫恢复的患者基因，并代表可用于促进免疫恢复的药物的新靶点。这项建议还将确定艾滋病毒感染者应该接受哪些药物治疗，以最大限度地提高他们的免疫恢复程度。