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，以培养候选人成为一名独立的流行病学研究人员，专注于艾滋病毒神经发病机制和艾滋病毒感染儿童的神经认知结果。该候选人将回答关于抗逆转录病毒治疗（ART）在保存和挽救神经认知发育方面的益处的关键问题，以及作为hiv诱导的神经认知障碍的潜在机制的系统性单核细胞激活的作用。该培训计划建立在候选人在HIV发病机制、儿科HIV和流行病学方面的研究专长基础上，并将提高她对HIV神经发病机制及其与儿童认知发展关系的理解。该提案提供了一个基础，候选人将开发一个独立的研究项目，在儿科艾滋病毒，重点是神经发病机制和神经流行病学。该指导计划将肯尼亚研究项目的儿童艾滋病毒研究人员与华盛顿大学在神经病学和神经心理学方面的卓越机构之间的高效合作结合起来。明尼苏达大学在非洲神经认知评估方面的额外专业知识将补充这一指导计划。研究计划-艾滋病毒损害儿童的神经认知发育，尽管抗逆转录病毒治疗，一些神经认知缺陷仍可能持续存在。特别是，尽管对治疗有成功的病毒学和免疫反应，但持续的免疫激活可能限制抗逆转录病毒治疗的益处。我们将利用现有的和新的儿科HIV队列进行新的神经认知研究。在目标1中，我们将确定婴儿期早期抗逆转录病毒治疗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较晚诊断并开始抗逆转录病毒治疗并随后随访的儿童中神经认知缺陷的患病率及其相关因素。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，并且较长的系统性单核细胞激活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，以优化艾滋病毒感染儿童的神经认知结果。这次培训机会将会带来

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. PUBLIC HEALTH RELEVANCE: Sarah Benki-Nugent, MS, PhD is a Senior Fellow in the Division of Allergy and Infectious Diseases, Department of Medicine at the University of Washington. The proposed career development plan and research will provide the Candidate with mentored learning in HIV neuropathogenesis and neuropsychology while conducting research to determine the extent to which antiretroviral therapy can salvage neurocognitive abilities and to identify modifiable cofactors for residual neurocognitive deficits in African HIV-infected children. Findings from this research will form the basis of the Candidate's independent career focused on improvement of neurocognitive outcomes in HIV-infected African children.