The impact of host genetics and stimulant use on neurocognition in HIV+ adults.

描述（由申请人提供）：在拟议的研究中，我们将研究非法兴奋剂使用如何影响人类免疫缺陷病毒（HIV）感染个体的神经认知功能的纵向过程，以及宿主遗传变异如何调节这一过程。虽然已经确定HIV感染和兴奋剂使用都会导致神经认知障碍，并且这些影响是附加的甚至是协同的，但这两个因素之间的相互作用关系随着时间的推移尚未得到检验。此外，虽然宿主遗传学在艾滋病毒/艾滋病进展中的作用在过去几年中受到越来越多的关注，但其对神经认知缺陷的进展和特征的贡献仍有待确定。为了解决这个问题，我们将采用两种遗传关联方法。首先，我们将利用候选基因方法，对HIV+和HIV-个体进行大样本（N = 1000），重点研究影响多巴胺（DA）代谢和活性的多态性。这种神经递质与HIV相关的神经认知障碍（HAND）和慢性兴奋剂滥用的认知后遗症的神经发病机制有关。此外，研究表明，da相关基因的功能多态性可以通过潜在神经生理学的改变来影响神经心理功能，这种情况发生在与神经艾滋病患者相似的大脑区域。因此，检查da相关多态性可能为解释HIV+吸毒者神经心理结果和进展的个体间差异增加了关键的知识层。在这项探索性研究中，我们还将研究与神经生物学和免疫功能相关的其他基因变异，包括ApoE、脑源性神经营养因子和肿瘤坏死因子。在第二种方法中，我们将检查来自496个HIV+个体的全基因组关联（GWA）扫描的现有数据。我们将能够检测超过555,000个单核苷酸多态性（SNPs），以检测与神经认知表型相关的新基因，例如HAND的进展和诊断。如此大规模的HAND神经发病机制的遗传分析尚未开展。拟议的研究将使用多中心艾滋病队列研究（MACS），这是一项对HIV+个体的自然史和临床结果的纵向研究。神经心理学，精神病学和病毒学数据的队列主要是白种人，男同性恋者定期收集。数据存在于HIV+和HIV-个体，以及具有不同兴奋剂使用模式的个体。液体可用于DNA提取和基因分型。拟建的研究小组由精神病学遗传学、神经心理学、神经艾滋病和统计学方面的专家组成，他们已经成功地开展了类似的研究，并使用了MACS数据。这些研究结果将有助于更好地了解HAND的神经发病机制，确定药物靶点，并最终提高艾滋病毒感染者的生活质量。这些调查的结果将立即转化为公共卫生工作。具体来说，它们将进一步阐明对HAND神经发病机制的理解。此外，识别HAND神经发病机制中的宿主遗传因素将有助于开发特异性药物治疗，最终提高艾滋病毒感染者的生活质量。

DESCRIPTION (provided by applicant): In the proposed study we will examine how illicit stimulant use affects the longitudinal course of neurocognitive functioning in individuals infected with human immunodeficiency virus (HIV), and how host-genetic variation modulates this. While it is has been established that both HIV infection and stimulant use result in neurocognitive impairment, and that these effects are additive or even synergistic, the interactive relationship between these two factors as it evolves over time has not yet been examined. Further, while the role of host- genetics in the progression of HIV/AIDS has received growing attention during the past few years, its contribution to the progression and characteristics of neurocognitive deficits over time remains to be determined. To address this, we will employ two genetic association methods. First, we will utilize a candidate gene approach with a large sample (N = 1000) of HIV+ and HIV- individuals that will focus on polymorphisms that affect the metabolism and activity of dopamine (DA). This neurotransmitter is implicated in the neuropathogenesis of HIV- associated neurocognitive disorders (HAND) and cognitive sequelae of chronic stimulant abuse. Further, research has shown that functional polymorphisms in DA-related genes can affect neuropsychological functioning via alterations in underlying neurophysiology, and that this occurs in brain regions similar to those affected in neuroAIDS. Therefore, examination of DA-related polymorphisms may add a critical tier of knowledge for explaining inter-individual variation in neuropsychological outcomes and progression among HIV+ drug users. In this exploratory study, we will also examine variants of other genes associated with neurobiological and immune functioning, including ApoE, brain-derived neurotrophic factor, and tumor necrosis factor-alpha. In the second approach, we will examine existing data from a genome-wide association (GWA) scan of 496 HIV+ individuals. We will be able to examine over 555,000 single nucleotide polymorphisms (SNPs) in an effort to detect novel genes associated with neurocognitive phenotypes, such as progression and diagnosis of HAND. Such a large scale genetic analysis of HAND neuropathogenesis has yet to be conducted. The proposed study will use the Multicenter AIDS Cohort Study (MACS), a longitudinal study of the natural history and clinical outcomes in HIV+ individuals. Neuropsychological, psychiatric, and virologic data on cohort of largely Caucasian, gay males are collected at regular intervals. Data exist for both HIV+ and HIV- individuals, as well as individuals with varying stimulant use patterns. Fluids are available for DNA extraction and genotyping. The proposed research team consists of experts in psychiatric genetics, neuropsychology, NeuroAIDS, and statistics with proven ability by successfully carrying out similar studies and to work with MACS data. The results of these investigations will lead to greater understanding of the neuropathogenesis of HAND, identification of pharmaceutical targets, and ultimately greater quality of life for those infected with HIV. The results of these investigations will be immediately translatable to public health efforts. Specifically, they will further illuminate understanding of the neuropathogenesis of HAND. Further, the identification of host- genetic factors in the neuropathogenesis of HAND will enable development of specific pharmaceutical treatments, ultimately leading to greater quality of life for those infected with HIV.