Immune Activation and Neurodegeneration in HIV Infection and Heavy Drinking

项目总结/摘要 本K23提案的目的是使早期职业调查员能够建立独立的研究 艾滋病毒感染和酒精使用障碍的转化神经科学计划。K23研究集中在三个方面 NIAAA战略计划中的高优先领域：1）艾滋病毒-酒精相互作用; 2）肠道-大脑轴; 3）免疫 酒精的影响。8 -10 HIV慢性全身性炎症的一个主要因素是微生物易位 (MT)，肠道产物进入循环的异常运动。11，12已知大量饮酒也会导致MT 13 -15在HIV中，MT和免疫活化生物标志物独立地预测认知障碍， 这表明这些过程有助于神经退行性变。16 -18事实上，大脑白色的退化 这是艾滋病毒感染和大量饮酒的标志性伤害，单独或同时发生。 白色物质变性对艾滋病毒感染者构成严重的健康风险，特别是那些参与艾滋病毒感染的人。 危险的饮酒研究1将调查是否大量饮酒化合物MT和免疫激活， HIV感染以及这些过程是否预示着随着时间的推移白色物质的退化。研究1结合了新的 免疫生物标志物测定，并对来自纵向研究的神经成像和物质使用数据进行二次分析 布朗酒精研究中心关于艾滋病毒的研究（2 P01 AA 019072）。在180名按艾滋病毒分层的参与者中， 和大量饮酒状态（42例对照; 68例仅HIV; 34例仅ETOH; 36例HIV+ETOH），血浆样本和酒精 在基线、3个月、6个月和12个月收集使用数据。脑白色物质的评估使用扩散张量 基线和12个月时的成像。K23项目将使用重新储存的血浆样本来检验以下假设： MT和免疫反应的特异性标志物将预测大量饮酒、HIV及其 科摩罗。结果将有助于1）开发HIV和酒精相关脑的外周生物标志物 损害; 2）特别是艾滋病毒感染者更安全地使用酒精的指导方针。研究2将解决关键问题 通过调查两个关键的背景因素来了解酒精对急性免疫影响的知识差距：1）酒精剂量 和2）习惯性大量饮酒，先前的研究将其与肠道通透性过高联系起来。13，24，25研究2使用了一种 2 × 3设计，饮酒状态（轻度、重度）作为受试者间因素，饮料条件（安慰剂，0.35 g/kg，0.60 g/kg）作为受试者内因素。30名参与者（15名轻度饮酒者，15名重度饮酒者）将接受所有条件 以随机平衡的方式。将测量MT和免疫应答的生物标志物的变化。 对HIV阴性个体的研究2将提供酒精诱导的免疫紊乱的标准数据， 为今后计划对艾滋病毒阳性者进行的研究提供信息。候选人已经召集了一个非常合格的 导师团队在神经科学，行为和免疫学研究艾滋病毒和酒精使用的专业知识。 K23培训计划将使申请人能够在转化神经科学领域建立独立的职业生涯 通过以下方面的指导培训研究艾滋病毒-酒精相互作用：1）艾滋病毒特异性临床研究; 2）免疫 艾滋病毒和酒精使用的过程; 3）艾滋病毒的神经生物学; 4）基于实验室的酒精研究机制。

PROJECT SUMMARY / ABSTRACT The objective of this K23 proposal is to enable an early-career investigator to establish an independent research program in translational neuroscience of HIV infection and alcohol use disorders. The K23 studies focus on three high-priority areas within NIAAA's strategic plan: 1) HIV-alcohol interactions; 2) the gut-brain axis; and 3) immune effects of alcohol.8-10 A major contributor to chronic systemic inflammation in HIV is microbial translocation (MT), the abnormal movement of gut products into circulation.11, 12 Heavy alcohol use also is known to cause MT and inflammation.13-15 In HIV, MT and immune activation biomarkers independently predict cognitive impairment, suggesting these processes contribute to neurodegeneration.16-18 Indeed, degeneration of the brain's white matter is a hallmark injury of both HIV infection and heavy alcohol use, independently and in co-occurrence.19-23 White matter degeneration poses a serious health risk for people living with HIV, particularly those who engage in hazardous drinking. Study 1 will investigate whether heavy drinking compounds MT and immune activation in HIV infection and whether these processes predict white matter degeneration over time. Study 1 combines new immune biomarker assays with secondary analysis of neuroimaging and substance use data from a longitudinal study by Brown's Alcohol Research Center on HIV (ARCH; 2P01AA019072). In 180 participants stratified on HIV and heavy drinking status (42 control; 68 HIV only; 34 ETOH only; 36 HIV+ETOH), plasma samples and alcohol use data were collected at baseline, 3, 6, and 12 months. Brain white matter was assessed using diffusion tensor imaging at baseline and 12 months. Using reposited plasma samples, the K23 project will test the hypothesis that specific markers of MT and immune response will predict WM degeneration in heavy drinking, HIV, and their comorbidity. Results will contribute to 1) development of peripheral biomarkers of HIV- and alcohol-related brain damage; 2) guidelines for safer alcohol use specifically in people living with HIV. Study 2 will address critical knowledge gaps on alcohol's acute immune effects by investigating two key contextual factors: 1) alcohol dose and 2) habitual heavy drinking, linked by previous research to intestinal hyperpermeability.13, 24, 25 Study 2 uses a 2 x 3 design with drinking status (light, heavy) as between-subjects factor and beverage condition (placebo, 0.35 g/kg, 0.60 g/kg) as within-subjects factor. Thirty participants (15 light, 15 heavy drinkers) will receive all conditions in randomized, counterbalanced fashion. Change in biomarkers of MT and immune response will be measured. Study 2 with HIV-negative individuals will provide normative data on alcohol-induced immune perturbations to inform planned future studies with HIV-positive individuals. The candidate has assembled a superbly qualified mentor team with expertise in neuroscientific, behavioral, and immunological research on HIV and alcohol use. The K23 training plan will enable the applicant to establish an independent career in translational neuroscience research on HIV-alcohol interactions through mentored training in 1) HIV-specific clinical research; 2) immune processes in HIV and alcohol use; 3) HIV neurobiology of HIV; 4) mechanistic, lab-based alcohol research.