"Plasma and cellular immune biomarkers of Kaposi's sarcoma in HIV-1 suppressed patients"

“HIV-1 抑制患者中卡波西肉瘤的血浆和细胞免疫生物标志物”

基本信息

批准号：
10431995
负责人：
Salum Juma Lidenge
金额：
$ 9.22万
依托单位：
MUHIMBILI UNIVERSITY/ ALLIED HLTH SCIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431995
关键词：
Acquired Immunodeficiency Syndrome Address Africa South of the Sahara Age B-Lymphocytes Biological Markers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caring Cell Compartmentation Cell Count Cell Differentiation process Cells Chronic Clinical Management Defect Development Diagnostic Disease Early Diagnosis Gene Expression Profiling HIV HIV-1 Human Herpesvirus 8 Immune Immune response Immune system Immunologic Markers Immunologics Immunophenotyping Immunotherapeutic agent Immunotherapy Individual Infection Institutes Kaposi Sarcoma Lead Link Malignant Neoplasms Mediating Metabolic Pathway Morbidity - disease rate Oceans Patients Pattern Persons Plasma Prevalence Proteome Proteomics Recovery Reporting Resolution Role T cell reconstitution T cell response T-Cell Depletion T-Lymphocyte Tanzania Treatment Efficacy Urine Viral Viral Load result anergy antiretroviral therapy base cell mediated immune response chemotherapy co-infection comparative cytokine cytotoxic CD8 T cells early detection biomarkers enzyme linked immunospot assay exhaustion experience high risk immune reconstitution insight metabolome metabolomics mortality potential biomarker reconstitution recruit response sex transcriptome transcriptome sequencing transcriptomics treatment center tumor vaccine development

项目摘要

Abstract Despite more than a decade of widespread antiretroviral therapy (ART) implementation, Kaposi’s sarcoma (KS) remains the most common malignancy in people living with HIV-1/AIDS, in whom it causes significant morbidity and mortality [1]. Beyond a requirement for KSHV infection, the mechanisms underlying KS development are poorly understood. KS prevalence is high in people living with HIV-1 where it associates with CD4+ T-cell depletion. Thus, CD4+ T-cell functional dysregulation has been suggested to lead to KS development. Indeed, following successful ART, there is reconstitution of CD4+ T-cells [17] which often leads to KS resolution. In contrast, KS in patients with high CD4+ T-cells and low HIV-1 PVL [4–7] have been described, suggesting immune defects beyond CD4 T-cell reconstitution. In HIV-1 PVL suppressed patients, it is possible that there exist quantitative or qualitative differences in CD4+ T-cells between patients that develop KS and those who remain asymptomatic. These differences might limit the ability of CD4+ T-cells to provide help to B-cells and cytotoxic CD8+ T-cell. Alternatively, CD4+ T-cells might be fully functional in HIV-1 PVL suppressed patients but the defect is in the cytotoxic CD8+ T-cell compartment in those with KS. Chronic antigenic stimulation could induce CD8+ T-cells to states of exhaustion or anergy making them non-responsive to KSHV infected cells and KS tumors. Importantly, there are no biomarkers of KS control or its absence that can be used to identify individuals that are high risk for KS despite HIV-1 control. Our group and others have shown dysregulation of metabolic pathways in KS tumors [11–14]. Since altered metabolites often correlate with disease, identification of plasma and or urine metabolites that differentiate HIV-suppressed patients with and without KS could prove to be important KS biomarkers. Therefore, the objective of this proposal is to recruit Tanzanian HIV-1 PVL suppressed patients presenting with KS at ORCI, and age and sex-matched co- infected but asymptomatic controls from nearby CTCs in order to define immune responses and metabolomic profiles that differentiate the two groups. The hypothesis is that, distinct metabolomic and immune responses differentiate reconstituted HIV-1 suppressed patients experiencing KS from otherwise matched asymptomatic controls. Transcriptional profiling of relevant immune cell subsets and metabolomics/proteomic analysis of plasma and urine will provide mechanistic insight into the bases for the differential metabolomics/proteomics and immune responses. Therefore, the proposed study has potential to identify biomarkers for KS diagnostics, treatment management, or to identify potential immunotherapeutic or vaccine development strategies.

抽象的尽管抗逆转录病毒疗法 (ART) 已广泛实施十多年，但卡波西肉瘤 (KS) 仍然是 HIV-1/艾滋病感染者中最常见的恶性肿瘤，对他们来说，它会导致严重的后果。除了 KSHV 感染的必要条件外，KS 的发病机制也是如此。人们对 KS 的发展知之甚少，而 HIV-1 感染者的 KS 患病率很高。 CD4+ T 细胞耗竭因此，CD4+ T 细胞功能失调被认为会导致 KS。事实上，成功的 ART 后，CD4+ T 细胞会重建 [17]，这通常会导致疾病的发生。相比之下，CD4+ T 细胞高且 HIV-1 PVL 低的患者中的 KS 已得到解决。描述，表明在 HIV-1 PVL 抑制的患者中，CD4 T 细胞重建之外的免疫缺陷。出现这种情况的患者之间的 CD4+ T 细胞可能存在数量或质量差异 KS 和那些仍然无症状的人，这些差异可能会限制 CD4+ T 细胞提供服务的能力。有助于 B 细胞和细胞毒性 CD8+ T 细胞，或者，CD4+ T 细胞可能在 HIV-1 PVL 中发挥全部功能。但慢性 KS 患者的细胞毒性 CD8+ T 细胞区室存在缺陷。抗原刺激可能会诱导 CD8+ T 细胞进入疲惫或无反应状态，使其失去反应重要的是，没有 KS 控制的生物标志物或缺乏 KS 控制的生物标志物。尽管我们的团队和其他人已经控制了 HIV-1，但可用于识别 KS 高风险个体。显示 KS 肿瘤中代谢途径的失调[11-14]，因为代谢物通常相互关联。与疾病相关的血浆和/或尿液代谢物的鉴定可将 HIV 抑制的患者与没有 KS 也可能被证明是重要的 KS 生物标志物。因此，本提案的目的是坦桑尼亚招募了在 ORCI 中出现 KS 的 HIV-1 PVL 抑制患者，年龄和性别相匹配来自附近 CTC 的受感染但无症状的对照，以确定免疫反应和代谢组学区分这两个群体的假设是，不同的代谢和免疫反应。将经历 KS 的重组 HIV-1 抑制患者与其他匹配的无症状患者区分开来相关免疫细胞亚群的转录谱和代谢组学/蛋白质组学分析。血浆和尿液将为差异代谢组学/蛋白质组学的基础提供机制洞察因此，拟议的研究有可能确定 KS 诊断的生物标志物，治疗管理，或确定潜在的免疫治疗或疫苗开发策略。