Clinical Phenotyping: Pediatric HIV and TB Cohort

项目摘要 艾滋病毒/艾滋病仍然是撒哈拉以南非洲发病率和死亡率的主要原因， 脆弱艾滋病毒疾病发展为艾滋病是复杂的。虽然研究在成人，主要是西方 种群已经清楚地证明了宿主遗传因素在这一进程中的一致作用，宿主 遗传因素影响撒哈拉以南地区人群的疾病进展，特别是非洲儿童 人口，在很大程度上仍然未知。同样，结核病（TB）仍然是导致 撒哈拉以南非洲的发病率和死亡率，特别是那些同时感染艾滋病毒的人。因此有 迫切需要找到管理和诊断结核感染的新的有效战略。暴露于M。 结核病-结核病的病原体-通常导致活动性结核病（ATB），潜伏性结核病 感染（LTBI）或无TB。然而，这些结果背后的驱动机制还没有得到很好的理解， 使得用于检测它们的诊断不精确，特别是在儿童中。尽管如此， 越来越多的证据表明，宿主基因组因素发挥了重要作用，并可用于诊断。 先进的基因组技术为研究宿主提供了宝贵的机会 艾滋病毒和结核病在撒哈拉以南非洲儿童的疾病进展的遗传学，这是科学的核心， 非洲基因组学合作网络（CAfGEN）-一个H3非洲合作中心， 乌干达、博茨瓦纳、斯威士兰和美国的机构。在上一个颁奖期间，尽管 面对不可避免的挑战，CAfGEN能够使用下一代测序来识别候选基因， 影响儿科HIV进展和TB疾病进展;利用科学研究来建立和 在乌干达和博茨瓦纳发展基因组学能力、技术和专业知识;并有效地让当地 在解决与基因组学研究有关的伦理、法律的和社会问题（ELSI）方面， 在下一个资助期内，CAfGEN将通过以下方式在这些成就的基础上再接再厉：a）扩大 儿童艾滋病毒和结核病在儿童中的进展，包括新的人群和新的科学; B）提供 在非洲大陆进行更多的基因组学和生物信息学培训; c）协助六名博士生， 接受了两年的人类遗传学研究生培训，以过渡到独立的研究人员， （d）继续采用创新办法，让当地社区参与， 解决与非洲基因组学研究有关的ELSI问题。在这样做的时候，CAfGEN将贡献新颖和 重要的机制见解儿科艾滋病毒和艾滋病毒结核病的进展，同时创造一个可持续的， 协同，知识渊博的非洲基因组联盟能够改变非洲健康的未来 非洲大陆-H3非洲倡议的最终目标。

Project Summary HIV/AIDS remains a major cause of morbidity and mortality in sub-Saharan Africa and children are particularly vulnerable. The progression of HIV disease to AIDS is complex. Although studies in adult, mostly Western populations have clearly demonstrated a consistent role for host genetic factors in this progression, the host genetic factors influencing disease progression in sub-Saharan populations, and in particular, pediatric African populations, remains largely unknown. In the same way, tuberculosis (TB) remains a significant cause of morbidity and mortality in sub-Saharan Africa, particularly in those co-infected with HIV. Hence there is a pressing need to find new and effective strategies for managing and diagnosing TB infections. Exposure to M. tuberculosis – the causative agent of TB – typically results in either active TB disease (ATB), latent TB infection (LTBI), or no TB. The driving mechanisms behind these outcomes, however, are not well understood, making the diagnostics employed for their detection imprecise, particularly in children. Nonetheless, there is growing evidence that host genomic factors play a prominent role, and can be diagnostically exploited. The availability of advanced genomic technologies presents a valuable opportunity to investigate the host genetics of HIV and TB disease progression in sub-Saharan children, and this is at the scientific core of the Collaborative African Genomics Network (CAfGEN) – an H3Africa Collaborative Center spanning six institutions in Uganda, Botswana, Swaziland, and the United States. During the previous award period, despite unavoidable challenges, CAfGEN was able to use next-generation sequencing to identify candidate genes influencing pediatric HIV progression and TB disease progression; leverage scientific studies to establish and develop genomics capacity, technology, and expertise in Uganda and Botswana; and effectively engage local communities in addressing ethical, legal and social issues (ELSI) related to genomics research. In the next grant period CAfGEN will build on these achievements by a) expanding genomics studies of pediatric HIV and TB disease progression in children to include new populations and new science; b) providing additional genomics and bioinformatics training on the continent; c) assisting the six PhD students who received two-years of graduate training in human genetics to transition into independent investigators in their home countries; and d) continuing the use of innovative approaches to engage local communities in addressing ELSI related to genomics research in Africa. In so doing, CAfGEN will contribute novel and important mechanistic insights to pediatric HIV and HIV-TB disease progression, whilst creating a sustainable, synergistic, knowledgeable African genomic alliance capable of transforming the future of health on the African continent – the ultimate goal of the H3Africa Initiative.