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

项目总结/摘要 卡波西肉瘤（KS）已成为撒哈拉以南非洲地区成人和儿童最常见的恶性肿瘤之一 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年前的地方性KS报告最近被KS发病率的大幅增加所掩盖 与非洲的艾滋病疫情同时发生。关于临床和生物学上的区别， 艾滋病相关和地方性艾滋病无关的儿科KS之间的关系。比较与KS截然不同的体验 在美国/欧洲与非洲（成人和儿童），人们必须考虑这样的假设， 非洲地方性KSHV感染的独特病毒学特征导致了临床观察结果的差异 地区之间。随着为数百万艾滋病毒感染者提供联合抗逆转录病毒疗法（cART）的努力不断加强， 在过去十年中，非洲儿童感染KS的人数增加，儿科KS已成为一个重要的公共卫生问题。为一体 KS是非洲许多地区最常见的儿童癌症，已成为第二大最常见的儿童癌症。 马拉维伯基特淋巴瘤之后的恶性肿瘤。虽然早期的观察报告儿童KS的死亡率很高， 尽管有cART，但由于以下原因，KS儿童的存活率最近增加到近60%， 提高对儿科KS独特临床特征的认识，并改善基础设施， 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 终身抗逆转录病毒治疗机制。作为最常见的儿童恶性肿瘤之一， KSHV的病原体，增加对儿科KS的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局的机会。我们对生物学知之甚少 儿童KS的基础，但其独特的临床特征肯定有生物学联系，可能不仅 为患者提供治疗策略，但我们对KSHV肿瘤发生的分子机制的整体见解。 因此，本提案的目标是研究儿童KSHV转录谱的差异， 与马拉维地方性KS的HIV阴性患者相比， 非洲艾滋病毒感染率高的地区。我们的假设是，不同的生物机制驱动不同的 与HIV阴性地方性KS相比，HIV相关KS的病理学和治疗反应模式。这项建议 目的是评估获得的HIV阴性地方性和HIV相关儿科KS患者的KSHV转录谱， 来自两个队列-（1）利用现有标本的回顾性横断面队列，和（2）前瞻性 纵向队列病毒学特征（KSHV转录谱模式、KSHV病毒 负荷和白细胞介素-6水平）和包括治疗结果在内的临床特征。最后， 该建议旨在确定KSHV病毒学的独特特征，以及它们如何影响KSHV病毒学与 儿科KS的临床变异。这些信息可能会启发治疗KS，KSHV和其他疾病的新途径。 相关的恶性肿瘤，并最终改善全球患者的长期结局。

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.