HIV and Psychiatric Comorbidity: Selected Genetic and Epigenetic Factors

描述(申请人提供)：拟议研究的总体目标是确定HIV-1感染者大脑中阿片能、应激反应、5-羟色胺和多巴胺能系统基因的特定基因变异和表观遗传修饰与HIV-1疾病进展的关系。许多感染HIV-1病毒的人患有共病的精神疾病，包括抑郁、焦虑和冲动行为。宿主遗传因素-可以改变艾滋病毒-1感染，并已被证明影响患精神疾病的脆弱性。阿片类药物在体外促进HIV-1在免疫和神经胶质细胞中的复制，可能是通过增加趋化因子CCR5(HIV-1进入细胞的辅助受体之一)的水平和抑制宿主HIV保护因子来实现的。从国家神经艾滋病组织联盟获得的大脑样本中，将调查u-阿片受体基因OPRM1和CCR5的基因型和表达模式之间的关系。同时还将检查抑郁、焦虑、非典型应激反应、冲动和冒险行为，这些都可能是药物滥用/成瘾的表现。为了确定HIV-1感染进展的外围标志，将研究表观遗传因素在大脑和淋巴细胞中的作用，这些因素可能调节与传染性和冒险行为相关的关键基因，这些因素可能与精神疾病和滥用/成瘾有关。在一项使用女性机构间艾滋病毒研究储存库样本的大型研究中，我们将调查5-羟色胺、多巴胺和阿片能系统基因多态与HIV-1感染进展的关系。这些变异与冲动和冒险行为与HIV-1疾病进展的关系将被研究。阐明与精神疾病和滥用/成瘾等复杂疾病的易感性相关的多态可能为未来的临床研究提供基础。此外，这些研究可能确定遗传变异和表观遗传机制在HIV-1感染进展中的作用，并可能指出HIV-1疾病合并精神疾病的药物治疗靶点。从这项研究中获得的信息应该有助于减轻HIV-1感染与共病的精神疾病的痛苦。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to determine the relationship of both specific gene variants and epigenetic modification of genes of the opioidergic, stress response, serotonergic, and dopaminergic systems in the brain of HIV-1 infected subjects with the progression of HIV-1 disease. Many individuals infected with HIV-1 suffer from comorbid psychiatric illnesses, including depression, anxiety, and impulsive behaviors. Host genetic factors-can modify HIV-1 infection and have been shown to affect the vulnerability to develop psychiatric illnesses. Opioids promote HIV-1 replication in immune and glial cells in vitro, presumably by increasing levels of the chemokine CCR5 (one of the coreceptors for HIV-1 entry into the cell) and by the suppression of host HIV-protective factors. The relationship between the genotype and expression patterns of the mu-opioid receptor gene, OPRM1, and CCR5 in brain samples obtained from the National NeuroAIDS Tissue Consortium will be investigated. Comorbid depression, anxiety, atypical stress responsivity, impulsivity, and risk-taking behaviors, of which drug abuse/addiction may be a manifestation, will be examined. To identify peripheral markers for the progression of HIV-1 infection, the role of epigenetic factors in both brain and lymphocytes from individuals characterized as to psychiatric comorbidity and abuse/addiction, which may modulate key genes related to infectivity and risk-taking, will be examined. In a large study using samples from the Women's Interagency HIV Study repository, we will investigate the relationship between polymorphisms in genes of the serotonergic, dopaminergic and opioidergic systems with HIV-1 infection progression. The relationship of these variants with impulsivity and risk-taking to HIV-1 disease progression will be examined. Clarifying the functional relevance of polymorphisms associated with susceptibility to complex disorders such as psychiatric illnesses and abuse/addiction may provide the foundation for future clinical studies. Also, these studies may identify the role of genetic variants and epigenetic mechanisms in the progression of HIV- 1 infection and may point to targets for pharmacotherapy in HIV-1 disease with psychiatric comorbidity. The information gained from this research should help to alleviate the suffering of HIV-1 infection with comorbid psychiatric diseases.