Environmental determinants of KSHV transmission in rural Uganda

项目总结/摘要 卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体， 在人类疱疹病毒中的独特之处在于它在人群中并不普遍存在，而是表现出显著的 流行的地理热点，特别是在撒哈拉以南非洲（SSA）。此外， 在撒哈拉以南非洲地区，即使在同一人群中地理位置接近的地区之间，患病率也存在差异。 这有力地表明，存在可改变的环境因素，促进和维持高水平 我们认为，疟疾感染是一个关键的潜在因素。我们提供广泛的 支持儿童疟疾感染与KSHV之间相互作用的已发表和初步数据 血清阳性率我们假设儿童疟疾感染增加了他们对KSHV的易感性 通过改变免疫功能或扩大KSHV细胞靶点或两者。对于那些 已经感染KSHV的人，疟疾感染可能导致病毒重新激活， 外周血、更高的脱落频率或两者。乌干达农村地区的一般人口队列 是一项纵向研究，调查艾滋病毒流行的趋势和决定因素，以及非 传染病危险因素。我们发现GPC中KSHV血清阳性率是有史以来最高的 据报告，艾滋病毒/艾滋病感染率为90%以上，儿童在幼年时感染艾滋病毒/艾滋病（3岁时约为30%）。KSHV感染的早期年龄， 乌干达GPC的地方性疟疾传播和高水平的KSHV血清阳性率提供了 给了我们一个独特的机会来直接验证我们的假设我们将招募一名未来的婴儿 GPC内的队列确定恶性疟原虫对KSHV感染建立的影响; 表征KSHV感染前儿童的免疫表型，并评估恶性疟原虫对 KSHV重新激活。在这项提案中，我们将利用正在进行的关于KSHV的实质性研究计划 并将把拟议的工作嵌入乌干达农村长期存在的以人口为基础的队列中， 大量的现有数据。拟议的工作将解决以下方面的深刻知识差距： 影响KSHV传播的因素。这可能会在未来导致干预措施的发展， 减少传输，从而减少KS的负担。

PROJECT SUMMARY/ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS), is unique among human herpesviruses in that it is not ubiquitous in human populations, but rather shows marked geographic hotspots in prevalence, being particularly common in sub-Saharan Africa (SSA). Moreover, there is variation in prevalence even between geographically proximate locations within the same population in SSA. This strongly suggests the presence of modifiable environmental factors that facilitate and maintain high levels of transmission in SSA and we posit that malaria infection is a key underlying factor. We provide extensive published and preliminary data supporting an interaction between malaria infection in children and KSHV seroprevalence. We hypothesize that malaria infection in children increases their susceptibility to KSHV through alterations in immune function or expansion of KSHV cellular targets or both. For children that are already KSHV infected, malaria infection could lead to viral reactivation resulting in higher viral loads in peripheral blood, higher frequency of shedding or both. The General Population Cohort (GPC) in rural Uganda is a longitudinal study investigating the trends and determinants of the HIV epidemic, as well as non- communicable disease risk factors. We found that KSHV seroprevalence in the GPC is among the highest ever reported (>90%) and children are infected at an early age (~30% by 3 years). The early age of KSHV infection, the endemic malaria transmission and the high levels of KSHV seroprevalence in the Ugandan GPC provides us with a unique opportunity to directly test our hypothesis. We will do this by enrolling a prospective infant cohort within the GPC determining the effect of P. falciparum on the establishment of KSHV infection; characterizing immune phenotype in children prior to KSHV infection and evaluate effects of P. falciparum on KSHV reactivation. In this proposal, we will capitalise on an ongoing substantive research program on KSHV and will embed the proposed work within a long-standing population-based cohort in rural Uganda, with a substantial body of existing data. The proposed work will address the profound knowledge gap regarding factors that influence KSHV transmission. This may, in the future, lead to the development of interventions to reduce transmission and thereby reduce the burden of KS.