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

摘要 尽管十多年来广泛实施的抗逆转录病毒疗法(ART)，卡波西肉瘤 (KS)仍然是HIV-1感染者/艾滋病患者中最常见的恶性肿瘤，它会导致显著的 发病率和死亡率[1]。除了对KSHV感染的要求之外，KS背后的机制 人们对发展知之甚少。KS在HIV-1携带者中的患病率很高，在那里它与 CD4T细胞耗尽。因此，CD4T细胞功能失调被认为是导致KS的原因 发展。事实上，在成功的抗逆转录病毒治疗之后，有CD4T细胞的重建[17]，这通常导致 到KS分辨率。相比之下，高CD4T细胞和低HIV-1PVL患者的KS[4-7] 描述，表明免疫缺陷超越了CD4T细胞的重建。在HIV-1 PVL抑制的患者中，它 CD4T细胞可能在数量上或质量上存在差异 KS和那些仍然没有症状的人。这些差异可能会限制CD4T细胞提供 帮助B细胞和细胞毒CD8 T细胞。或者，在HIV-1PVL中，CD4T细胞可能是完全功能的 受抑的患者，但缺陷是在细胞毒性CD8 T细胞隔间的KS。慢性 抗原刺激可诱导CD8 T细胞进入耗竭或无能状态，使其无反应 对KSHV感染细胞和KS肿瘤的作用。重要的是，没有KS控制或其缺失的生物标志物 可用于识别尽管HIV-1得到控制但仍为KS高危个体。我们的团队和其他人 显示KS肿瘤的代谢途径失调[11-14]。因为改变的代谢物通常与 与疾病，识别血浆和/或尿代谢物，以区分艾滋病毒抑制患者与 如果没有KS，KS可能被证明是重要的KS生物标志物。因此，这项建议的目标是 招募坦桑尼亚HIV-1 PVL抑制在Orci出现KS的患者，年龄和性别匹配的共同 来自附近CTC的感染但无症状的对照，以确定免疫反应和代谢 区分这两组人的个人资料。假设是，不同的新陈代谢和免疫反应 重组HIV-1抑制的KS患者与其他匹配的无症状患者的鉴别 控制。相关免疫细胞亚群的转录图谱和代谢组学/蛋白质组学分析 血浆和尿液将提供对差异代谢组学/蛋白质组学基础的机械性洞察 和免疫反应。因此，这项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战略。

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.