Platelets Mediating Alcohol and HIV Damage

描述（由申请人提供）：本研究的设计认识到，酒精使用和HIV感染的并发症在全球范围内正在升级，并且关键问题是这些HIV感染者在其更有生产力的年龄中的免疫反应和认知能力显著受损。认识到免疫系统参与认知障碍的神经生物学机制，我们还将通过评估血小板和血小板相关因子（即血清素，PAF，BDNF）对免疫和认知功能障碍的影响来研究其作用。对这一潜在机制的支持基于我们的初步发现和证据，即1）HIV和酒精使用均影响血小板和血小板相关因子，并受其影响，2）血小板是神经递质和免疫调节剂的来源; 3）血小板下降与HIV疾病进展相关，4）血小板已被证明是研究CNS损害的良好外周模型。在过去的六年里，我们评估了酒精滥用和HIV感染对神经免疫系统的有害影响，在种族多样的临床样本中。拟议的应用程序将建立在我们以前的研究。使用基于观察性临床的纵向研究，我们将评估四组中的血小板、血小板相关因子、免疫和认知功能：危险和非危险饮酒的HIV感染受试者以及危险和非危险饮酒的HIV血清阴性受试者（n=540）。使用标准问卷，将获得详细的社会人口统计学、医疗、营养、酒精使用和HIV用药史。纵向随访的生物学指标（即酒精水平、血小板计数、血清素、脑源性神经营养因子、血小板激活因子、CD 4、CD 8、标志物或细胞凋亡、TNF病毒载量、营养状态、生化特征）将补充评价。认知功能将在基线、6、12和18个月时使用认知测试组合进行评估，该组合包含NIMH HIV神经心理评估方法工作组的建议。然后，我们将通过研究组建立血小板系统指标、认知能力和临床状态之间的横向和纵向受试者内关系。我们的长期目标是扩大与酒精/艾滋病毒损伤机制有关的生物医学知识。血小板减少及血小板相关因素对观察结果的影响。公共卫生相关性：总的来说，这些信息将扩大治疗干预的范围，这些干预可能用于增强或恢复因HIV感染和饮酒而改变的宿主防御机制和神经免疫调节。通过增加对血小板减少症在HIV发病机制中作用的新机制的理解，科学家可以操纵它们以获得治疗优势。

DESCRIPTION (provided by applicant): This study has been designed with the recognition that the concurrence of alcohol use and HIV infection are escalating worldwide, and of critical concern is the significantly impairing immune responses and cognitive performance among those HIV infected individuals in their more productive years. Recognizing the involvement of the immune system in the neurobiological mechanisms that underlie cognitive impairment, we will also investigate its action, through the evaluation of platelets and platelet associated factors (i.e. serotonin, PAF, BDNF) on both immune and cognitive dysfunction. Support for this potential mechanism is based upon our preliminary findings and evidence that 1) both HIV and alcohol use affect and are affected by platelets and platelet associated factors, 2) platelets are a source of neurotransmitters and immunomodulators; 3) platelet drops have been associated with HIV disease progression and 4) platelets have been proof a good peripheral model to study CNS compromise. Over the past six years, we have evaluated the deleterious effects of combined alcohol abuse and HIV infection over the neuroimmune system, in an ethnically diverse clinical sample. The proposed application will build upon our previous studies. Using an observational clinic based longitudinal study we will evaluate platelets, platelet associated factors, immune and cognitive function in four groups: hazardous and non-hazardous alcohol consuming HIV-infected subjects and hazardous and non-hazardous alcohol consuming HIV sero-negative subjects (n=540). Using standard questionnaires, a detailed sociodemographic, medical, nutritional, alcohol use and HIV medication history will be obtained. Biological measures (i.e. alcohol levels, platelet counts, serotonin, brain derived neurotrophic factors, platelet activator factor, CD4, CD8, markers or apoptosis, TNF viral load, nutrition status, biochemical profile) followed longitudinally will complement the evaluation. Cognitive function will be evaluated at baseline, 6, 12 and 18 months using a cognitive test battery that incorporates recommendations from the NIMH Workgroup on Neuropsychological Assessment Approaches in HIV. We will then establish cross-sectional and longitudinal within-subject relationships among platelets system measures, cognitive performance, and clinical status by study groups. Our long-term objectives are to extend biomedical knowledge related to mechanism mediating alcohol/HIV damage. magebocytopenia and platelet associated factors on the observations. PUBLIC HEALTH RELEVANCE: Collectively, this information will broaden the scope of therapeutic interventions that might be used to enhance or restore host defense mechanisms and neuroimmune modulation that have been altered as a result of HIV infection and drinking. By increasing understanding of the new mechanistic insights related to the role of thrombocytopenia in the pathogenesis of HIV, scientist can manipulate them to therapeutic advantage.