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.

与HIV相关的Kaposi肉瘤（KS），也称为流行病Kaposi肉瘤（EPKS），是领先的 撒哈拉以南非洲（SSA）的恶性肿瘤。它是因发病率和死亡率的十大恶性肿瘤之一 大多数SSA国家。美国国立卫生研究院的艾滋病临床和试验小组（ACTG） 美国已经制定了登台EPK的标准。该标准有3个类别，包括肿瘤（T; T0 vs.T1） 考虑了基于CD4计数的肿瘤，免疫状态（I; I0 vs.I1）的程度， 系统性疾病（S; S0 vs. S1）基于机会性感染和其他系统性 疾病。 EPK的治疗仅涉及抗逆转录病毒疗法（ART），以解决早期疾病（尤其是 T0阶段）和艺术加化学疗法，以用于更晚期疾病。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 治疗时的反应甚至会经历疾病进展。 T细胞免疫反应是 被认为在控制KS和Kaposi肉瘤相关的疱疹病毒中起着重要作用 （KSHV），KS的病因学剂。这是因为T细胞免疫的下降与 急剧增加（约20,000倍）在KS开发的风险中，而ART恢复T细胞免疫力 通过戒断ePK的给药，通过撤回生病性KS的病因免疫抑制剂 在许多情况下，与KS病变的回归有关。而且，代谢失调一直是 在KS肿瘤和KSHV感染的细胞中都观察到。我们的小组以前曾报道过脂质和 葡萄糖代谢途径在KS肿瘤中失调，最近未发表的有关 血浆代谢组表明通过KS状态簇生代谢物。 KSHV特异性T细胞是否 免疫和/或血浆代谢​​组与表现时不同的ACTG阶段相关，并且与 以前，在治疗过程中纵向纵向探索KS治疗结果。我们 假设较低的ACTG EPK阶段的基础抗KSHV T细胞反应高于 较高的EPK阶段。另外，我们假设对治疗的良好反应与更好的t有关 基线时的细胞响应，随着时间的流逝，这种响应在良好的响应者中有所改善，并有所改善 通过ART和/或通过ART和/或裂解KS肿瘤对KSHV蛋白的识别。 化学疗法导致更多接触KSHV抗原。我们还假设血浆 代谢组谱在基线和对治疗的响应时是差异的，并反映了 与阶段和对治疗反应有关的代谢失调。我们将检验这些假设 通过以下特定目的：1）确定KSHV特异性T细胞反应之间的差异 演示时的KS阶段和随访期间对治疗的反应； 2）比较血浆 KS阶段在演示中以及治疗响应者和较差的响应者之间进行的代谢组谱。