Project 2

神经激肽-1拮抗剂（SP拮抗剂）CP 96、345和阿瑞匹坦抑制单核细胞来源的HIV感染性。 巨噬细胞，来源于健康个体并在离体细胞培养物中研究。我们有 在IB期临床试验（IND 75558临床试验）中，将这些发现扩展到两周的体内环境 NCT 00428519）在具有可检测的病毒载量和CCR 5 HIV毒株的HIV感染受试者中， 正在等待这项盲法临床试验的结果。NKIR拮抗剂的拟议研究将是 使用通过另一个NIMH资助的招募获得的外周血样本进行 离体细胞研究（R 01-MH 082670，2008-2013，“抑郁症、抗抑郁药和HIV感染性”） 从抑郁和非抑郁HIV阴性的男性和女性获得。目标是确定 抑郁症是否会改变细胞对HIV感染的易感性。在我们长期的调查中， 我们已经观察到对NKIR拮抗剂（CP 96、345和阿瑞匹坦）的应答的差异， 来自健康供体的单核细胞衍生的巨噬细胞（MDM）对病毒攻击的易感性。在这 项目，我们将进一步研究选定的NKI R拮抗剂的抗病毒活性，靶向细胞来自 HIV感染的个体和细胞从具有不同程度抑郁的个体中进行体外研究， 由汉密尔顿抑郁量表和其他标准精神病学测量确定。我们假设 阿瑞匹坦抑制HIV进入MDM中并复制。我们进一步假设这种效应是通过 CCR 5下调。我们预测，抑郁症患者的MDM将感染一种 HIV离体模型更容易，并将显示出对NKIR拮抗剂的更好反应， 非抑郁症患者的细胞。我们进一步提出，抑郁症患者的自然杀伤细胞 相对于抑制性自然杀伤细胞的受损连接， NK 1 R受体拮抗剂的治疗将恢复这些功能。体外效率 将测定来自抑郁受试者的细胞中的NKIR拮抗剂。

The neurokinin-1 antagonists (SP antagonist) CP96,345 and aprepitant inhibit HIV infectivity of monocytederived macrophages, derived from healthy individuals and studied in ex vivo cell cultures. We have extended these findings to a two-week in vivo setting in a Phase IB clinical trial (IND 75558 Clinical Trial NCT00428519) in HIV-infected subjects with detectable viral loads and CCR5 HIV strains, and we are awaiting the results of this ongoing blinded clinical trial. The proposed study of NKIR antagonists will be performed using peripheral blood samples to be obtained through recruitment with another NIMH funded study (R01-MH082670, 2008-2013, "Depression, Antidepressants and HIV infectivity") in ex vivo cells obtained from depressed and non-depressed HlV-negative men and women. The goal is to determine whether depression alters susceptibility of cells to HIV infectivity ex vivo. In our long-standing investigations, we have observed differences in resopnise to NKIR antagonists (CP96,345 and aprepitant) related to susceptibility of monocyte-derived macrophages (MDMs) from healthy donors to viral challenge. In this project, we will further investigate anti-viral activity of selected NKI R antagonists targeted against cells from HIV-infected individuals and cells investigated ex viVo from individuals with different levels of depression as determined by Hamilton Depression scales and other standard psychiatric measures. We hypothesize that aprepitant inhibits HIV entry and replication in MDMs. We further hypothesize that this effect is mediated through CCR5 down-regulation. We predict that MDMs from subjects with depression will be infected with an HIV ex vivo model more readily and will demonstrate better responses to NKIR antagonists compared with cells from non-depressed subjects. We further propose that Natural Killer cells from subjects with depression will have impaired Natural Killer cell functions relative to impaired ligation of inhibitory Natural Killer cell receptors and that treatment with NK1R antagonists will restore these functions. The ex vivo efficiacy of NKIR antagonists in cells from depressed subjects will be determined.