Impact of HIV, immune activation, and ART on child neurodevelopment in Kenya

描述（由申请人提供）：该提案描述了一个5年的职业发展和研究计划，以培养候选人作为一个独立的流行病学研究人员，重点是艾滋病毒感染儿童的艾滋病毒神经发病机制和神经认知结果。候选人将回答抗逆转录病毒治疗（ART）对保护和挽救神经认知发育的益处，以及系统性单核细胞激活作为HIV诱导的神经认知障碍的潜在机制的作用等关键问题。培训计划建立在候选人在艾滋病毒发病机制，儿科艾滋病毒和流行病学的研究专长，并将提高她对艾滋病毒神经发病机制及其与儿童认知发展的关系的理解。该提案提供了一个基础，候选人将制定一个独立的研究计划，在儿科艾滋病毒，重点是神经发病机制和神经流行病学。该指导计划整合了肯尼亚研究计划的儿科艾滋病毒研究人员与华盛顿大学神经病学和神经心理学方面的卓越机构之间的高效合作。明尼苏达大学在非洲的神经认知评估方面的其他专业知识将补充这一指导计划。研究计划-艾滋病危害儿童的神经认知发育和一些神经认知缺陷可能会持续，尽管ART。特别是，持续的免疫激活，尽管成功的病毒学和免疫反应的治疗，可能会限制ART的好处。我们将利用现有的和新的儿科艾滋病队列进行新的神经认知研究。在目标1中，我们将确定在婴儿期开始的早期ART在多大程度上保留了长期的神经认知，并将确定神经认知缺陷的患病率、类型和辅助因素。在目标2中，我们将确定在儿童期后期诊断的儿童中神经认知缺陷的患病率和相关因素，这些儿童开始ART并随后随访。在目标3中，我们将确定病毒、免疫和免疫激活对各组HIV感染和治疗儿童神经认知结果的相对影响。我们假设早期和晚期ART可以挽救神经认知结果，并且系统性单核细胞激活的持续时间较长与神经认知缺陷的严重程度相关。我们预计，这些研究的数据将为干预措施提供信息，以优化艾滋病毒感染儿童的神经认知结果。这次培训机会将导致 候选人开发一个独立的翻译研究计划，重点是艾滋病毒感染儿童神经认知障碍的机制和预防。

DESCRIPTION (provided by applicant): This proposal describes a 5 year career development and research plan to train the Candidate as an independent epidemiologic researcher with a focus on HIV neuropathogenesis and neurocognitive outcomes in HIV-infected children. The Candidate will answer key questions addressing the benefit of antiretroviral therapy (ART) on preservation and salvage of neurocognitive development, and the role of systemic monocyte activation as a potential mechanism of HIV-induced neurocognitive impairment. The training plan builds on the Candidate's research expertise in HIV pathogenesis, pediatric HIV and epidemiology, and will improve her understanding of HIV neuropathogenesis and its relation to cognitive development in children. The proposal provides a foundation with which the Candidate will develop an independent research program in pediatric HIV, with an emphasis on neuropathogenesis and neuroepidemiology. The mentoring plan integrates a highly productive collaboration between pediatric HIV researchers from the Kenya Research Program with institutional excellence in neurology and neuropsychology at the University of Washington. Additional expertise in neurocognitive assessments in Africa from the University of Minnesota will complement this mentoring plan. Research Plan - HIV compromises neurocognitive development in children and some neurocognitive deficits may persist despite ART. In particular, sustained immune activation, in spite of successful virological and immune response to treatment, may limit the benefit of ART. We will utilize existing and novel pediatric HIV cohorts to undertake new neurocognitive studies. In Aim 1, we will determine the extent to which early ART started in infancy preserves long-term neurocognition and will identify prevalence, types and cofactors of neurocognitive deficits. In Aim 2, we will determine prevalence and correlates of neurocognitive deficits in children diagnosed later in childhood who initiate ART and are followed thereafter. In Aim 3, we will determine the relative influence of viral, immunologic and immune activation on neurocognitive outcomes in each group of HIV-infected and treated children. We hypothesize that early- and late-ART can salvage neurocognitive outcomes and that longer duration of systemic monocyte activation will correlate with severity of neurocognitive deficits. We anticipate that data from these studies will inform interventions to optimize neurocognitive outcomes in children with HIV. This training opportunity will result in the Candidate developing an independent translational research program focused on mechanisms and prevention of neurocognitive impairment in HIV-infected children.