Hiv-1 Infection: Central Serotonergic Activity and its Health Implications

描述（由申请人提供）：这项R21探索性申请测试了HIV-1+病例不同脑区血清素能活性将受到不利影响的假设。HIV-1在初次感染后立即进入中枢神经系统（CNS），并以不同的浓度定位于不同的大脑区域，导致进行性神经变性。有人提出，HIV-1诱导的高单胺活性神经元（如5-羟色胺，5- ht）的退化可能具有广泛的健康影响，包括抑郁症和其他神经精神疾病、神经异常和神经认知障碍。抑郁症是大量HIV-1感染者中最常见的神经精神疾病之一，影响他们的生活质量，干扰对治疗的坚持，并且是疾病进展和死亡的危险因素。HIV-1感染中抑郁症的病因是复杂的，可能涉及许多因素，包括神经生物系统的功能障碍，特别是中枢血清素系统。然而，到目前为止，对HIV-1感染的中枢血清素能机制及其与抑郁的关系的调查仍在调查中，并且知之甚少。为了研究HIV-1感染个体的中枢血清素能机制，需要死后脑组织以及相应个体一生中抑郁评估的相关数据。近年来，由美国国立卫生研究院赞助的国家神经艾滋病组织联盟（NNTC）建立的脑库已经完成了这两个要求，这使得HIV-1+和HIV-1病例的不同大脑区域的特征样本的可用性成为可能，并为本项目中提出的研究提供了机会。研究了40例成年男性和女性(HIV-1+病例，N=25；HIV-1-病例N=15)，年龄25-55岁，属于三个种族（高加索人、非洲裔美国人、西班牙裔美国人），他们在一生中同意参加NNTC项目。假设与HIV-1病例的相同脑区相比，HIV-1+病例的上述脑区中5-HT及其代谢物5-羟基吲哚乙酸（5-HIAA）的水平会降低；5-HT和5-HIAA水平与HIV-1+患者大脑同一区域的病毒载量以及相应HIV-1+个体一生中评估的抑郁评分呈负相关。我们建议检测在死亡前至少6个月使用贝克抑郁量表（BDI）评估的HIV-1+个体的这些大脑区域的5-HT和5-HIAA水平，并研究在生命中接受或未接受HAART治疗的HIV-1+个体的相同大脑区域中央区5- ht活性与病毒载量之间的关系。这一探索性R-21项目的研究结果将描述与5-HT活性相关的特定区域对HIV-1攻击的脆弱性。此外，这些数据将为RO1应用提供机会，以研究HIV-1感染病例不同脑区的5-羟色胺能机制的其他参数，包括5-HT受体和5-HT转运体/s，并探索新的相关治疗策略的可能性。公共卫生相关性：这项R-21提案探讨了HIV-1感染对HIV/AIDS患者死后大脑不同区域中枢神经系统血清素活性的影响。有人提出，HIV-1诱导涉及血清素能活动的大脑各个区域的神经退行性变。我们将确定5-羟色胺及其代谢物5-HIAA在脑干中叶核中的水平，在那里5-羟色胺能神经元的细胞体位于和5-羟色胺能合成，以及在各种其他区域的高度神经支配的5-羟色胺能投射，并参与许多生理和行为功能。本研究结果将显著提高我们对HIV-1诱导的中枢血清素能缺陷的影响的理解，这可能有助于设计干预策略，将有助于改变中枢血清素能活性，提高HIV-1感染者的生活质量。

DESCRIPTION (provided by applicant): This R21 exploratory application tests the hypothesis that the serotonergic activity will be adversely impacted in different brain regions of HIV-1+ cases. HIV-1 enters the central nervous system (CNS) immediately after initial infection and localizes itself with variable concentration in different brain regions, resulting in progressive neurodegeneration. It is proposed that HIV-1 induced degeneration of neurons of high monoaminergic activity, such as that of serotonin (5- hydroxytryptamine, 5-HT) may have a wide range of health implications, including depression and other neuropsychiatric disorders, neurological abnormalities, and neurocognitive impairment. Depression is one of the most common neuropsychiatric disorders in a large number of HIV-1 infected individuals, and affects their quality of life, interferes in adherence to treatment, and is a risk factor for disease progression, and mortality. The etiology of depression in HIV-1 infection is found to be complex and may involve a number of contributing factors including dysfunctions of neurobiological systems particularly, the central serotonin system. However, to date, investigations on the central serotonergic mechanisms and their relationship with depression in HIV-1 infection has remained under investigated and poorly understood. In order to investigate the central serotonergic mechanisms in HIV-1 infected individuals, the postmortem brain tissues, as well as the data related with assessment of depression during life of the corresponding individuals are required. In recent years, both of these requirements have been accomplished by the brain banks established by the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC), which has made possible the availability of well characterized samples of different brain regions of HIV-1+ and HIV-1- cases, and has provided the opportunity for investigations such as those proposed in this project. It is proposed to investigate the central serotonergic activity in the postmortem tissue samples from different brain regions {raphe nuclei, hypothalamus, hippocampus, basal ganglia (caudate nucleus, putamen, globus pallidus), substantia nigra, amygdala and fronto-cortical regions (cingulate and subgenual cortical areas) as well as CSF} of a total of 40 adult men and women (HIV-1+ cases, N=25; HIV-1- cases N=15), age 25-55 years, belonging to the three ethnic groups (Caucasian, African Americans, Hispanics), who consented during life to participate in the NNTC project. It is hypothesized that the levels of 5-HT as well as its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) will be decreased in the above mentioned brain regions of HIV-1+ cases, compared to that in the same brain regions of HIV-1- cases; and that the 5-HT and 5-HIAA levels will be negatively correlated with the viral load in the same brain regions of HIV-1+ cases, as well as with depression scores assessed during life of the corresponding HIV-1+ individuals. We propose to examine the 5-HT and 5-HIAA levels in these brain regions of HIV-1+ individuals who were assessed during life, at least six months before death, for depression using Beck Depression Inventory (BDI), and investigate the relationship between the central regional 5-HTactivity and viral load in the same brain regions of HIV-1+ individuals, who were treated or not treated with HAART during life. The findings from this exploratory R-21 project will delineate the specific regional vulnerability to assault by HIV-1 with respect to 5-HT activity. Furthermore, the data will provide us with an opportunity for an RO1 application to investigate the other parameters of serotonergic mechanisms including 5-HT-receptors and 5-HT transporter/s in different brain regions of HIV-1 infected cases, and for exploring the possibility for new relevant strategies for treatment. PUBLIC HEALTH RELEVANCE: This R-21 proposal explores the impact of HIV-1 infection on the central nervous system serotonergic activity in different regions of post mortem brains of HIV/AIDS cases. It is proposed that HIV-1 induces neurodegeneration of various areas of the brain that are involved in serotonergic activity. We will determine the levels of 5-HT and its metabolite, 5-HIAA in the brain stem raphe nuclei, where the cell bodies of serotonergic neurons are located and 5-HT is synthesized, as well as in various other regions which are highly innervated with serotonergic projections, and are involved in a number of physiological and behavioral functions. The findings from this study will significantly enhance our understanding of the impact of HIV-1 induced central serotonergic deficits, that may be helpful in designing the intervention strategies that will contribute to modify the central serotonergic activity, and improve the quality of life of HIV-1 infected individuals.