Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 (NK1-R) Antagonists

神经激肽受体（NK 1 R）是P物质偏好性受体，是一种新的治疗靶点， 神经艾滋病神经激肽-1受体拮抗剂（NK 1 RA）具有抗病毒活性、正性免疫调节活性和抗肿瘤活性。 影响和神经行为影响。我们已经在单核细胞中证明了显著的体外抗HIV活性- NK 1 RA衍生的巨噬细胞，其包括FDA许可的药物阿瑞匹坦。抗病毒效果是 部分通过CCR 5下调介导。阿瑞匹坦能穿过血脑屏障。阿瑞匹坦是 在恒河猴中是安全的，我们正在进行一项为期两周的盲态IB期临床安全性试验， HIV感染者中的阿瑞匹坦（NCT 00428519）。在这个新的项目应用程序中，我们提出了一个 一系列新的研究将确定NK 1 R的作用机制。有三个互动 临床前和临床项目，其目标是开发用于神经艾滋病的NK 1 RA疗法：1）细胞 机制-脑和免疫系统中的神经激肽-1R拮抗剂; 2）免疫机制-抗 神经激肽-1R拮抗剂在抑郁症中的HIV作用;和5）神经激肽-1R的IB期临床试验 拮抗剂-阿瑞匹坦与利托那韦加强和NK 1 R拮抗功效的直接证明，以及两个核心：A） 给药;和C）定量药理学和生物统计学。优化NKI RA在 神经艾滋病治疗的建议和计划项目包括基本的，转化，和临床艾滋病毒 速激肽（P物质）和NK 1 RA的研究。小约瑟夫·斯托克斯的调查员。R1，CHOP， 宾夕法尼亚大学医学院（UPenn Schools of Medicine）儿科，精神病学和医学）和Westat。费城 ACTU和IMPAACT CTU、Penn-CHOP CFAR和Penn CTSU促进了拟议的互动。这些 分子学、免疫学、药理学和从实验室到临床的项目都致力于这一新的治疗靶点 用于神经艾滋病治疗 相关性（见说明）： 提出了一项综合临床前/临床计划（IPCP），将NK 1 RA用作抗HIV药物， 神经艾滋病这类受体拮抗剂穿过血脑屏障。这种NK 1 RA具有作为 抗HIV病毒剂，提高先天免疫力（自然杀伤细胞），并具有积极的神经行为 方面的影响. NK 1 RA是一种潜在的治疗神经艾滋病的新方法。

The neurokinin receptor (NK1R), the substance P-preferring receptor, is a novel therapeutic target for neuroAIDS. Neurokinin-1 receptor antagonists (NK1RA) have antiviral activity, positive immunomodulatory effects and neurobehavioral effects. We have demonstrated significant ex vivo anti-HIV activity in monocyte- derived macrophages of NK1RA, which include the FDA licensed drug, aprepitant. The antiviral effect is mediated, in part, through CCR5 down-regulation. Aprepitant crosses the blood-brain barrier. Aprepitant is safe in rhesus macaques, and we have an ongoing two-week blinded Phase IB clinical safety trial of aprepitant in HIV-infected humans (NCT00428519). In this new program-project application, we propose a novel series of studies which will determine the mechanism of action of NK1R. There are three interactive preclinical and clinical projects, which target the development of NK1RA therapy for neuroAIDS: 1) Cellular Mechanisms-Neurokinin-1 R Antagonists in the Brain and Immune System; 2) Immune Mechanisms-Anti- HIV Actions of Neurokinin-1 R Antagonists in Depression; and 5) Phase IB Clinical Trial of Neurokinin-1 R Antagonist-Aprepitant with ritonavir boost and direct proof of NK1R antagonism efficacy, and two Cores: A) Administration; and C) Quantitative Pharmacology and Biostatistics. The optimization of the use of NKI RA in neuroAIDS therapy is proposed and the program-project encompasses basic, translational, and clinical HIV studies of tachykinin (substance P) and NK1RA. The investigators from the Joseph Stokes, Jr. Rl, CHOP, the UPenn Schools of Medicine (Depts. of Pediatrics, Psychiatry, & Medicine) and Westat. The Philadelphia ACTU and IMPAACT CTU's, Penn-CHOP CFAR, and Penn CTSU foster the proposed interactions. These molecular, immunologic, pharmacologic, and bench-to-bedside projects address this novel therapeutic target for neuroAIDS treatment. RELEVANCE (See Instructions): An integrated pre-clinical/clinical program (IPCP) is proposed to use NK1RA as anti-HIV agents in neuroAIDS. This class of receptor antagonists crosses the blood brain barrier. This NK1RA has activity as an antiviral HIV agent that improves innate immunity (Natural Killer cells) and has positive neurobehavioral effects. NK1RA are a potential novel therapy for neuroAIDS.