Project 2

项目2

• 批准号: 10598772
• 负责人: John T West
• 金额: $ 18.71万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598772
• 关键词: AIDS clinical trial group; AIDS related cancer; AIDS therapy; AIDS with Kaposi' s sarcoma; Africa; Africa South of the Sahara; Antigens; Biological Markers; CD4 Lymphocyte Count; Categories; Cells; Clinical; Country; Coupled; Cytolysis; Cytotoxic Chemotherapy; Data; Defect; Development; Disease; Disease Progression; Etiology; Exposure to; Fatty Acids; Glucose; Glycolysis; Growth; HIV; HIV Infections; HIV therapy; Herpesviridae Infections; Homeostasis; Human Herpesvirus 8; Iatrogenic Kaposi' s Sarcoma; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Incidence; Individual; Infection; Kaposi Sarcoma; Lesion; Lipids; Malignant Neoplasms; Mentors; Metabolic; Metabolic Pathway; Metabolism; Oceans; Oncology; Opportunistic Infections; Outcome; Oxidative Phosphorylation; Participant; Pathway interactions; Patients; Persons; Plasma; Play; Prevalence; Prognostic Marker; Proteins; Recurrence; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Stage Grouping; Staging; Surrogate Markers; T cell response; T-Lymphocyte; Tanzania; Teaching Hospitals; Testing; Therapeutic; Therapeutic immunosuppression; Time; Treatment outcome; United States National Institutes of Health; Universities; Viral; Withdrawal; Withholding Treatment; Zambia; advanced disease; antiretroviral therapy; career development; chemotherapy; co-infection; experience; follow-up; glucose metabolism; immune function; immune reconstitution; immunological status; improved; inter-institutional; lipid metabolism; metabolome; metabolomics; mortality; neoplastic; neoplastic cell; neutralizing antibody; prevent; programs; responders and non-responders; response; restoration; transcriptomics; treatment responders; treatment response; tumor; tumor metabolism; tumorigenesis

HIV-associated Kaposi sarcoma (KS), also known as epidemic Kaposi sarcoma (EpKS), is a leading malignancy in sub-Saharan Africa (SSA). It is among the top 10 malignancies by incidence and mortality in most SSA countries. The AIDS Clinical and Trials Group (ACTG) at the National Institutes of Health in the US has developed a criteria for staging EpKS. This criteria has 3 categories including tumor (T; T0 vs. T1) which considers the extent of the tumor, immune status (I; I0 vs. I1) which is based on CD4 counts, and systemic illness (S; S0 vs. S1) which is based on presence of opportunistic infections and other systemic illnesses. Treatment of EpKS involves antiretroviral therapy (ART) alone for early-stage disease (especially T0 stage), and ART plus chemotherapy for more advanced disease. Treatment outcomes for both treatment approaches are variable, with some individuals responding favourably while others have no response or even experience disease progression while on treatment. The T cell immune response is thought to play an important role in the control of both KS and Kaposi sarcoma-associated herpes virus (KSHV), the etiologic agent for KS. This is because a decline in T cell immunity is associated with a dramatic increase (~20,000-fold) in risk of KS development, while restoration of T cell immunity by ART administration for EpKS and by withdrawal of the causative immunosuppressive agent for iatrogenic KS is associated with regression of KS lesions in many instances. Also, metabolic dysregulation has been observed in both KS tumors and KSHV-infected cells. Our group has previously reported that lipid and glucose metabolism pathways are dysregulated in KS tumors, and more recent unpublished data on plasma metabolomes suggests a clustering of metabolites by KS status. Whether KSHV-specific T cell immunity and/or plasma metabolomes correlate with the different ACTG stages at presentation, and with KS treatment outcomes longitudinally during treatment has not been extensively explored previously. We hypothesize that lower ACTG EpKS stages have a higher underlying anti-KSHV T cell response than higher EpKS stages. Also, we hypothesize that a good response to treatment is associated with a better T cell response at baseline, and this response improves over time in good responders, with improved recognition of KSHV proteins after immune reconstitution with ART and/or lysis of KS tumors by chemotherapy resulting in more exposure to KSHV antigens. We also hypothesize that the plasma metabolomic profiles are differential at baseline and by response to treatment, and reflect the extent of metabolic dysregulation associated with stage and response to treatment. We will test these hypotheses through the following specific aims: 1) Determine differences in KSHV-specific T cell responses between KS stages at presentation and by response to treatment during follow-up; and 2) Compare plasma metabolomic profiles by KS stage at presentation and between treatment responders and poor responders.

HIV 相关卡波西肉瘤 (KS)，也称为流行性卡波西肉瘤 (EpKS)，是一种主要的 撒哈拉以南非洲（SSA）的恶性肿瘤。按发病率和死亡率计算，该病位居前 10 位恶性肿瘤之列。 大多数撒哈拉以南非洲国家。美国国立卫生研究院艾滋病临床和试验小组 (ACTG) 美国制定了 EpKS 分期标准。该标准有 3 个类别，包括肿瘤（T；T0 与 T1） 考虑肿瘤的范围、基于 CD4 计数的免疫状态（I；I0 与 I1），以及 全身性疾病（S；S0 与 S1），基于机会性感染和其他系统性感染的存在 疾病。 EpKS 的治疗涉及单独针对早期疾病（尤其是 T0 期），以及针对更晚期疾病的 ART 加化疗。两者的治疗结果 治疗方法多种多样，有些人反应良好，而另一些人则没有反应 治疗期间出现反应，甚至经历疾病进展。 T细胞的免疫反应是 被认为在控制 KS 和卡波西肉瘤相关疱疹病毒方面发挥重要作用 (KSHV)，KS 的病原体。这是因为 T 细胞免疫力下降与 发生 KS 的风险急剧增加（约 20,000 倍），同时通过 ART 恢复 T 细胞免疫力 EpKS 的给药和医源性 KS 的致病免疫抑制剂的撤药是 在许多情况下与 KS 病变的消退相关。此外，代谢失调 在 KS 肿瘤和 KSHV 感染的细胞中均观察到。我们课题组之前曾报道过脂质和 KS 肿瘤中葡萄糖代谢途径失调，最近未发表的数据 血浆代谢组表明代谢物按 KS 状态聚集。是否为KSHV特异性T细胞 免疫和/或血浆代谢​​组与就诊时的不同 ACTG 阶段相关，并且与 之前尚未广泛探讨治疗期间纵向的 KS 治疗结果。我们 假设较低的 ACTG EpKS 阶段比其他阶段具有更高的潜在抗 KSHV T 细胞反应 更高的 EpKS 阶段。此外，我们假设对治疗的良好反应与更好的 T 相关。 基线时的细胞反应，并且这种反应在良好反应者中随着时间的推移而改善，并且改善 通过 ART 免疫重建和/或 KS 肿瘤裂解后识别 KSHV 蛋白 化疗导致更多地接触 KSHV 抗原。我们还假设等离子体 代谢组学特征在基线和治疗反应方面存在差异，反映了代谢组学的变化程度 与阶段和治疗反应相关的代谢失调。我们将测试这些假设 通过以下具体目标： 1) 确定 KSHV 特异性 T 细胞反应的差异 就诊时和随访期间对治疗的反应确定 KS 阶段； 2) 比较血浆 就诊时的 KS 阶段以及治疗反应者和反应不良者之间的代谢组学特征。