Epigenetic and Psychosocial Drivers of NeuroHIV in HIV+ South African Adolescents

 描述(由申请人提供)：DNA甲基化(DNaM)是一种表观遗传过程，对神经发育和整个生命周期的神经功能至关重要。DNaM的异常会导致发育、神经退行性和精神障碍。我们发现，HIV+成人改变了脑和外周血单核细胞中的dNaM，导致生物衰老加速。围生期感染艾滋病毒(PHIV+)的儿童神经发育迟缓和持续性神经认知功能障碍的风险增加。在这项研究中，我们研究了dNaM在PHIV+青少年神经认知发展中的作用，同时也考虑了重要的心理社会、医学、病毒学和其他因素。这项研究的直接目标是描绘这些不同因素之间在PHIV+青少年神经认知障碍发病机制中的复杂关系。中间目标是利用所获得的信息来制定干预战略，旨在改善 艾滋病病毒携带者儿童成年后的生活。这项研究的长期目标是开发一种生物标记物，用于目前隐藏的由艾滋病毒引起的神经病理过程，以便为高危青年提供适当的干预。这项研究将考虑一系列已知的影响神经发育的环境因素，包括压力、抗逆转录病毒(ARV)药物的使用、经济逆境、医疗合并症以及家庭/家庭环境。它将利用开普敦青少年抗逆转录病毒队列(CTAAC)的现有资源，从而最大限度地提高效率和成本效益，同时将人类受试者的负担降至最低。横向和纵向目标的结合将使研究结果能够快速转化，并真实描述由艾滋病毒引起的表观遗传失调造成的神经发育和认知差异。此外，产生的全基因组甲基化数据可用于加强CTAAC的其他研究部门，最大限度地实现潜在投资回报。我们还加入了能力建设的元素，资助加州大学洛杉矶分校的一名博士后研究员接受加州大学洛杉矶分校的生物统计学培训。这项研究是通过两个团队的合作进行的：开普敦大学团队目前正在对200名艾滋病毒阳性青少年和50名艾滋病毒青少年进行CTAAC神经学分研究，通过扩散张量成像、全面的神经心理测试和儿童心理社会因素评估，将提供所有数据和生物样本，以及神经成像和儿科神经艾滋病毒方面的专门知识。加州大学洛杉矶分校的团队在表观遗传生物统计学方法和神经艾滋病毒的基因组研究方面拥有广泛的专业知识，他们将处理DNA样本并进行统计分析。

 DESCRIPTION (provided by applicant): DNA methylation (DNAm), an epigenetic process, is critical for neurodevelopment and for neurologic functioning throughout the lifespan. Aberrations in DNAm result in developmental, neurodegenerative, and psychiatric disorders. We have discovered that HIV+ adults have altered DNAm in both brain and peripheral blood mononuclear cells, resulting in accelerated biological aging. Perinatally HIV-infected (PHIV+) children are at increased risk of neurodevelopmental delay and lasting neurocognitive dysfunction. In this study, we examine the role of DNAm in the neurocognitive development of PHIV+ adolescents, while also considering important psychosocial, medical, virologic, and other factors. The immediate goal of this study is to delineate the complex relationship between these various factors in the pathogenesis of neurocognitive deficits in PHIV+ adolescents. The intermediate goal is to utilize the information gained to develop intervention strategies aimed at improving the lives of PHIV+ children as they progress into adulthood. The long term aim of this study is to develop a biomarker of currently concealed neuropathological processes that result from HIV, so that appropriate interventions can be provided to at-risk youths. This study will consider a host of environmental factors known to impact neurodevelopment, including stress, antiretroviral (ARV) medication use, economic adversity, medical comorbidities, and home/family environment. It will leverage the extant resource of the Cape Town Adolescent Antiretroviral Cohort (CTAAC), thereby maximizing efficiency and cost effectiveness, while minimizing human subjects' burden. The combination of cross sectional and longitudinal aims will allow fast translation of the findings and true characterization of neurodevelopmental and cognitive divergences resulting from epigenetic dysregulation due to HIV. In addition, the genome-wide methylation data generated can be used to enhance other research arms of the CTAAC, maximizing the potential return of investment. We also include a capacity building element by funding a postdoctoral fellow from UCT to be trained in biostatistics by UCLA researchers. This study is possible through the collaboration of two teams: The University of Cape Town team, which is currently carrying out the CTAAC neuro sub-study involving 200 HIV+ and 50 HIV- adolescents with diffusor tensor imaging, comprehensive neuropsychological testing, and assessment of childhood psychosocial factors, will provide all data and biological samples, as well as expertise in neuroimaging and pediatric neuroHIV. The University of California - Los Angeles team, which has extensive expertise in epigenetic biostatistical methods and genomic investigations of neuroHIV will process DNA samples and conduct the statistical analyses.