Viral and Host Determinants of Cognitive Status in Vertically Transmitted HIV

项目摘要 本研究的目的是对HIV宿主和病毒动力学进行对照研究 在接受稳定的联合抗逆转录病毒治疗（cART）的垂直感染儿童中， 缅甸在东南亚进行的PREDICT试验的结果显示， 艾滋病病毒阳性的儿童垂直感染者。社会经济变量预测认知测验 在感染艾滋病毒的儿童和接触艾滋病毒但未感染病毒的儿童中的表现。努力 要确定HIV的神经发病机制，需要充分控制这些环境变量 已知会影响认知测试表现和ADL参与。大多数艾滋病毒阳性儿童 在缅甸，居住在私人资助的孤儿院，有标准化的照顾者地位，营养， 教育我们的初步工作揭示了这些接受cART的儿童中存在认知障碍， 与人口统计学匹配的健康对照（HIV-）相比，此外，40%的艾滋病毒+ 儿童表达CXCR 4辅助受体的优先使用，认知障碍的程度是 与表达CCR 5共受体的儿童相比，尽管CD 4 + T细胞亚群相似， 道理先前的研究表明，CXCR 4的利用与HIV+成人的认知能力较差有关， 晚期疾病，但从这些研究中还不清楚是否共受体亚型是喜欢认知 或者更简单地说，是疾病严重程度和认知障碍之间的相关变量。我们 初步数据表明，CXCR 4在降低脑完整性方面的机制作用独立于 晚期疾病，强调需要确定相关的免疫因素。从我们的工作 研究小组先前证明，循环单核细胞HIV含量，单核细胞亚群， 髓源性免疫介质是HIV相关神经认知功能障碍的关键机制 损伤本研究将探讨这些免疫机制和共受体向性 在垂直感染青年认知障碍相关的级联事件中。该信息 对于促进有针对性的治疗方法的发展以改善儿童的认知功能至关重要 垂直感染艾滋病病毒。我们将招募120名HIV+垂直感染儿童和青少年 年龄在8岁至15岁之间，年龄在60岁之间的艾滋病毒控制者与人口统计学匹配， 私人出资的保险公司。将完成神经心理学、病毒学和免疫学检测 以确定稳定cART背景下的儿科HIV神经发病机制。

PROJECT SUMMARY-ABSTRACT The purpose of the proposed study is conduct a controlled investigation of HIV host and viral dynamics on brain integrity in vertically infected children on stable combined antiretroviral therapy (cART) in Myanmar. Outcomes from the PREDICT trial in Southeast Asia revealed residual cognitive impairment among pediatric HIV+ individuals with vertical infection. Socioeconomic variables predicted cognitive test performance among infected children and children exposed to HIV but uninfected with the virus. Efforts to define the neuropathogenesis of HIV require adequate control of these environmental variables known to influence cognitive test performance and engagement in ADLs. The majority of HIV+ children in Myanmar reside in privately funded orphanages with standardized caregiver status, nutrition, and education. Our preliminary work reveals cognitive impairment in these children on cART with high CD4 count when compared to demographically matched healthy controls (HIV-). Further, 40% of the HIV+ children express preferential use of the CXCR4 co-receptor and the degree of cognitive impairment is greater among these children compared to those expressing the CCR5 co-receptor despite similar CD4 counts. Previous studies have associated CXCR4 utilization with worse cognition in HIV+ adults with advanced disease, but it is unclear from these studies if co-receptor subtype is liked to cognitive impairment or more simply a correlated variable between disease severity and cognitive impairment. Our preliminary data suggests a mechanistic role for CXCR4 on reduced brain integrity independent of advanced disease, emphasizing the need to identify the relevant immunological factors. Work from our team previously demonstrated that circulating monocyte HIV content, monocyte subpopulations, and myeloid-derived immunological mediators are key mechanisms of HIV-associated neurocognitive impairment. The present study will examine these immunological mechanisms and co-receptor tropism in the cascade of events related to cognitive impairment in vertically infected youth. This information is critical to facilitate the development of targeted treatments to improve cognitive function among children with vertically infected HIV. We will enroll 120 HIV+ vertically infected children and adolescents between the ages of 8 and 15 and 60 HIV- controls matched for demographics, and all residing in privately funded orphanages. Neuropsychological, virological, and immunological assays will be completed to determine pediatric HIV neuropathogenesis in the context of stable cART.