Environmental determinants of KSHV transmission in rural Uganda

项目摘要/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。 人类疱疹病毒的独特之处在于它不是在人类群体中普遍存在，而是表现出明显的 地理热点流行，在撒哈拉以南非洲(SSA)特别常见。此外，还有 在SSA的同一人口中，即使在地理上邻近的地点之间，患病率也存在差异。 这强烈地表明，存在促进和维持高水平的可改变的环境因素 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 已发表的初步数据支持儿童疟疾感染与KSHV之间的相互作用 血清阳性。我们假设儿童感染疟疾会增加他们对KSHV的易感性。 通过免疫功能的改变或KSHV细胞靶点的扩大，或两者兼而有之。对于儿童来说， 已经感染KSHV的疟疾感染可能导致病毒重新激活，导致更高的病毒载量 外周血，脱落频率较高或两者兼而有之。乌干达农村地区的一般人口队列(GPC) 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 传染病危险因素。我们发现在GPC中KSHV的血清阳性率是有史以来最高的之一 报告(90%)和儿童在早期(约30%到3岁)被感染。KSHV感染的早期， 地方性疟疾传播和乌干达GPC中高水平的KSHV血清阳性率提供了 我们有一个独一无二的机会来直接检验我们的假设。我们将通过招募一名未来的婴儿来实现这一点 GPC内确定恶性疟原虫对建立KSHV感染的影响的队列； 儿童感染KSHV前的免疫表型特征及恶性疟原虫对儿童免疫表型的影响 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以人口为基础的队列中，并将 大量的现有数据。拟议的工作将解决关于以下方面的深刻知识差距 影响KSHV传播的因素。这可能在未来导致制定干预措施，以 减少传输，从而减轻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.