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

摘要 尽管抗逆转录病毒治疗（ART）已经广泛应用了十多年， (KS)仍然是HIV-1/AIDS患者中最常见的恶性肿瘤， 发病率和死亡率[1]。除了KSHV感染的需要外，KS的潜在机制 发展知之甚少。KS在HIV-1感染者中的流行率很高， CD 4 + T细胞耗竭。因此，CD 4 + T细胞功能失调被认为是导致KS的原因之一。 发展事实上，在成功的ART之后，存在CD 4 + T细胞的重建[17]，这通常导致 KS决议。相比之下，具有高CD 4 + T细胞和低HIV-1 PVL的患者中的KS [4-7]已经被证实是高水平的。 描述，表明免疫缺陷超越CD 4 T细胞重建。在HIV-1 PVL抑制患者中， 在发展为恶性肿瘤的患者之间，CD 4 + T细胞可能存在定量或定性差异， KS和那些仍然无症状。这些差异可能限制了CD 4 + T细胞提供免疫应答的能力。 有助于B细胞和细胞毒性CD 8 + T细胞。或者，CD 4 + T细胞可能在HIV-1 PVL中具有完全功能， 抑制的患者，但缺陷是在细胞毒性CD 8 + T细胞室与KS。慢性 抗原刺激可诱导CD 8 + T细胞进入耗竭或无反应状态，使其无反应 KSHV感染的细胞和KS肿瘤。重要的是，没有KS对照的生物标志物或其缺失， 可用于识别尽管HIV-1得到控制但KS高风险的个体。我们的团队和其他人 显示KS肿瘤中代谢途径失调[11-14]。因为代谢物的改变往往与 与疾病，鉴定血浆和/或尿液代谢物，区分HIV抑制患者与 而没有KS则可以证明是重要的KS生物标志物。因此，本建议的目的是 招募坦桑尼亚HIV-1 PVL抑制患者，在ORCI时表现为KS，年龄和性别匹配， 感染但无症状的对照来自附近的CTC，以确定免疫应答和代谢组学 区分两个群体的特征。假设是，不同的代谢和免疫反应 区分发生KS的重组HIV-1抑制患者与其他匹配的无症状患者 对照相关免疫细胞亚群的转录谱分析和免疫细胞亚群的代谢组学/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理上的见解 和免疫反应。因此，拟议的研究有可能鉴定KS诊断的生物标志物， 治疗管理，或确定潜在的免疫或疫苗开发策略。

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.