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

描述(由申请人提供)：这份建议书描述了一项为期5年的职业发展和研究计划，旨在将候选人培训为一名独立的流行病学研究员，重点是艾滋病毒感染儿童的神经发病机制和神经认知结果。候选人将回答一些关键问题，涉及抗逆转录病毒疗法(ART)在保存和挽救神经认知发育方面的好处，以及系统性单核细胞激活作为艾滋病毒诱导的神经认知障碍的潜在机制的作用。该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方面的研究专长的基础上，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，候选人将在此基础上开发一个独立的儿科艾滋病毒研究计划，重点是神经发病机制和神经流行病学。该指导计划结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学和神经心理学方面的优秀机构之间的高成效合作。明尼苏达大学在非洲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-艾滋病毒损害了儿童的神经认知发展，尽管抗逆转录病毒治疗，一些神经认知缺陷可能会持续存在。特别是，持续的免疫激活，尽管对治疗有成功的病毒学和免疫反应，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毒队列进行新的神经认知研究。在目标1中，我们将确定早期ART在婴儿时期开始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，我们将确定在儿童时期较晚诊断的儿童中神经认知缺陷的患病率和相关性，这些儿童开始接受抗逆转录病毒治疗，并在此后进行跟踪。在目标3中，我们将确定病毒、免疫和免疫激活对每组HIV感染和治疗儿童的神经认知结果的相对影响。我们假设，早期和晚期抗逆转录病毒治疗可以挽救神经认知结果，更长的系统单核细胞激活持续时间将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，以优化艾滋病毒儿童的神经认知结果。这一培训机会将导致 开发一项独立的翻译研究计划的候选人，重点是艾滋病毒感染儿童的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.