(PQ5) Exploring the Biological Distinctions between HIV-related and Endemic Pediatric Kaposi Sarcoma in a Kaposi Sarcoma-Associated Herpesvirus-Endemic Region of Africa

(PQ5) 探索非洲卡波西肉瘤相关疱疹病毒流行地区艾滋病毒相关性和地方性小儿卡波西肉瘤之间的生物学差异

• 批准号: 9335144
• 负责人: Nader Kim El-Mallawany
• 金额: $ 21.49万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335144
• 关键词: AIDS with Kaposi' s sarcoma; Adolescent; Adult; Africa; Africa South of the Sahara; Awareness; Biological; Burkitt Lymphoma; Caring; Characteristics; Child; Childhood; Clinical; Collaborations; Data; Dedications; Diagnostic; Disease; Epidemic; Europe; Evaluation; Genetic Transcription; Goals; HIV; Hematopoietic Neoplasms; Herpesviridae; Herpesviridae Infections; High Prevalence; Human; Human Herpesvirus 8; Immune; Immunosuppression; In complete remission; Incidence; Interleukin-6; Kaposi Sarcoma; Laboratories; Link; Longitudinal cohort; Lymphatic Diseases; Malawi; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Measurement; Medical; Molecular; Molecular Profiling; North Carolina; Outcome; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Population; Positioning Attribute; Prevalence; Public Health; Publications; Publishing; Reporting; Research; Research Infrastructure; Resources; Specimen; Supportive care; Surface; Survival Rate; Therapeutic; Treatment Factor; Treatment outcome; United States; Universities; Variant; Viral; Viral Load result; Work; antiretroviral therapy; cancer cell; chemotherapy; cohort; experience; improved; insight; mortality; novel therapeutics; prospective; reconstitution; treatment program; treatment response; treatment strategy; tumorigenesis; virology

PROJECT SUMMARY/ABSTRACT Kaposi sarcoma (KS) has become one of the most common malignancies in sub-Saharan Africa in adults and children alike. Linked to the particularly high prevalence of Kaposi sarcoma herpesvirus (KSHV) infection in the region, early reports of endemic KS from fifty years ago have been recently overshadowed by the massive increase in KS incidence coinciding with the HIV epidemic in Africa. Very little has been established about the clinical and biological distinctions between HIV-related and endemic HIV-unrelated pediatric KS. Comparing the dramatically different experiences with KS in the United States/Europe with those in Africa (in both adults and children), one must consider the hypothesis that distinct virologic characteristics of endemic KSHV infection in Africa contribute to the divergence in clinical observations between regions. With increased efforts to deliver combination antiretroviral therapy (cART) to the millions of HIV- infected children in Africa over the past decade, pediatric KS has surfaced as an important public health issue. As one of the most common childhood cancers in many regions of Africa, KS has become the second most common pediatric malignancy in Malawi after Burkitt lymphoma. Although early observations reported high mortality rates in pediatric KS despite the availability of cART, the survival rate for children with KS has recently increased to nearly 60% due to increased awareness of the unique clinical features of pediatric KS combined with improved infrastructure, increased access to diagnostic, therapeutic and supportive care resources, and continued dedication to providing sustainable mechanisms for lifelong cART. As one of the most common childhood malignancies, and one with a readily identifiable causative agent in KSHV, increasing the focus on the pathophysiologic pathways in pediatric KS represents an incredible opportunity to improve long-term outcomes for large numbers of patients. Very little is known about the biological underpinnings of pediatric KS, yet its unique clinical characteristics must certainly have biological links that may not only inform treatment strategies for patients, but our overall insight into molecular mechanisms of KSHV oncogenesis. Therefore, the goal of this proposal is to examine the distinctions in the transcription profile of KSHV in children and adolescents with HIV-related KS compared to HIV-negative patients with endemic KS in Malawi, a KSHV-endemic region of Africa with high HIV prevalence. Our hypothesis is that distinct biological mechanisms drive different pathologies and treatment-response patterns in HIV-related KS compared to HIV-negative endemic KS. This proposal aims to evaluate the KSHV transcription profile of HIV-negative endemic and HIV-related pediatric KS patients obtained from two cohorts—(1) a retrospective cross-sectional cohort utilizing existing specimens, and (2) a prospective longitudinal cohort. Associations between virologic characteristics (KSHV transcription profile patterns, KSHV viral load, and interleukin-6 levels) and clinical characteristics including treatment outcomes will also be examined. Ultimately, this proposal seeks to determine the unique features of KSHV virology and how they influence the distinctions between clinical variants of pediatric KS. This information may enlighten new pathways for treating KS, KSHV, and other associated malignancies and ultimately improve long-term outcomes for patients worldwide.

项目摘要/摘要 卡波西肉瘤(KS)已成为撒哈拉以南非洲最常见的成人和儿童恶性肿瘤之一 一模一样。与该区域卡波西肉瘤疱疹病毒(KSHV)感染的特别高流行率有关， 50年前关于地方性KS的报道最近被KS发病率的大幅增加所掩盖 恰逢非洲的艾滋病毒流行。临床和生物学上的区别还很少建立起来。 HIV相关和地方性HIV无关的儿科KS。比较与KS截然不同的体验 在美国/欧洲和非洲(无论是成人还是儿童)，人们必须考虑这样一个假设 非洲地方性KSHV感染的独特病毒学特征导致了临床观察的差异 在地区之间。随着为数百万艾滋病毒患者提供联合抗逆转录病毒疗法(CART)的努力增加， 在过去十年里，在非洲受感染的儿童中，儿科KS已成为一个重要的公共卫生问题。作为以下项目之一 KS是非洲许多地区最常见的儿童癌症，已成为第二常见的儿科癌症 马拉维的Burkitt淋巴瘤后的恶性肿瘤。尽管早期的观察报告了儿童KS的高死亡率 尽管有CART，但KS儿童的存活率最近已上升到近60%，原因是 提高了对儿童KS独特临床特征的认识，并改善了基础设施 获得诊断、治疗和支持性护理资源，并继续致力于提供可持续的 终身购物车的机械装置。是最常见的儿童恶性肿瘤之一，也是一种容易识别的 KSHV中的致病因素，增加对儿童KS病理生理途径的关注代表了一个令人难以置信的 为大量患者提供改善长期结果的机会。对生物的了解很少 儿科KS的基础，但其独特的临床特征肯定有生物学联系，不仅可能 为患者提供治疗策略，但我们对KSHV肿瘤发生的分子机制的总体洞察。 因此，这项建议的目标是检查KSHV在儿童和儿童中转录谱的差异。 马拉维HIV相关KS青少年与HIV阴性KS地方性KS患者的比较 这是非洲艾滋病毒高流行的区域。我们的假设是，不同的生物机制驱动不同的 与HIV阴性的地方性KS相比，HIV相关KS的病理和治疗反应模式。这项建议 目的评估获得的HIV阴性、地方性和HIV相关的儿童KS患者的KSHV转录谱 来自两个队列-(1)利用现有样本的回溯性横断面队列，和(2)前瞻性队列 纵向队列。病毒学特征(KSHV转录图谱、KSHV病毒 也将检查包括治疗结果在内的临床特征(负荷和白介素6水平)。最终， 这项建议试图确定KSHV病毒学的独特特征以及它们如何影响 儿童KS的临床变异型。这些信息可能会启发治疗KS、KSHV和其他疾病的新途径 并最终改善世界各地患者的长期预后。