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相关的卡波西肉瘤（KS），也称为流行性卡波西肉瘤（EpKS），是一种主要的 撒哈拉以南非洲的恶性肿瘤（SSA）。它是世界上发病率和死亡率最高的10种恶性肿瘤之一。 大多数撒哈拉以南非洲国家。美国国立卫生研究院的艾滋病临床和试验小组（ACTG） 美国已经制定了EpKS的分期标准。该标准有3个类别，包括肿瘤（T; T0 vs. T1） 其考虑肿瘤的程度、基于CD 4计数的免疫状态（I; I 0 vs. I1），以及 全身性疾病（S; S 0 vs. S1），基于机会性感染和其他全身性疾病的存在 疾病。EpKS的治疗包括针对早期疾病（特别是晚期疾病）单独的抗逆转录病毒疗法（ART）。 T0期），以及ART加化疗用于更晚期的疾病。两者的治疗结果 治疗方法是可变的，有些人反应良好，而另一些人则没有 在治疗过程中出现反应或甚至出现疾病进展。T细胞免疫反应是 被认为在KS和卡波西肉瘤相关疱疹病毒的控制中起重要作用 （KSHV），KS的病原体。这是因为T细胞免疫力的下降与T细胞免疫力的下降有关。 KS发展风险急剧增加（约20，000倍），而ART恢复T细胞免疫 通过给予EpKS和撤回医源性KS的致病免疫抑制剂， 在许多情况下与KS病变的消退相关。此外，代谢失调已被 在KS肿瘤和KSHV感染的细胞中观察到。我们的小组以前曾报道，脂质和 葡萄糖代谢途径在KS肿瘤中失调， 血浆代谢组表明代谢物通过KS状态聚集。KSHV特异性T细胞 免疫和/或血浆代谢组与不同的ACTG阶段在介绍，并与 KS治疗结果纵向治疗期间尚未广泛探讨以前。我们 假设较低的ACTG EpKS分期具有比对照组更高的潜在抗KSHV T细胞应答， 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 在基线时的细胞应答，并且这种应答在良好应答者中随着时间的推移而改善， 在用ART免疫重建和/或通过抗逆转录病毒抗体裂解KS肿瘤后识别KSHV蛋白 化疗导致更多地暴露于KSHV抗原。我们还假设血浆 代谢组学特征在基线时和对治疗的反应存在差异，并反映了 与阶段和对治疗的反应相关的代谢失调。我们将检验这些假设 通过以下具体目的：1）确定KSHV特异性T细胞应答在 表现时的KS分期和随访期间对治疗的反应;和2）比较血浆 根据就诊时的KS分期以及治疗应答者和不良应答者之间的代谢组学特征。