Impact of Cannabis on Inflammation and Viral Persistence in Treated HIV/SIV

描述：全世界有3500万艾滋病毒感染者，改善这些人的健康面临着巨大的挑战。抗逆转录病毒疗法(ART)抑制艾滋病毒复制，从而预防艾滋病并降低总体死亡率；然而，ART不能完全恢复健康。事实上，尽管病毒血症得到了持续的抑制，但随着艾滋病毒残留的持续存在，个人不能停止抗逆转录病毒治疗，如果停止抗逆转录病毒治疗，病毒反弹是不可避免的。这种残留的艾滋病毒蓄积物与持续的炎症有关。大麻在美国是一种广泛使用的药物，大麻类化合物等大麻衍生物通常用于治疗癌症等严重情况下的恶心和恶病质。几项研究表明，大麻素具有改变体内免疫反应和减少炎症的倾向。我们假设，在抗逆转录病毒药物治疗的艾滋病毒感染背景下使用大麻可能会减少炎症和持久的艾滋病毒蓄积物。在这里，我们挑衅性地提出在人类身上测试这一假设，方法是测量每天报告使用大麻的艾滋病毒感染者与不使用大麻的艾滋病毒感染者的炎症、免疫力以及血液和胃肠道(GI)组织中的艾滋病毒蓄积量。此外，我们将在共培养中使用大麻素受体激动剂评估大麻素抗炎活性的体外机制。此外，我们将利用SIV感染的非人类灵长类动物模型来测试这一非传统想法的因果关系，方法是用大麻类药物治疗经ART治疗的SIV感染猕猴，以评估对SIV储存库和炎症的影响。凭借一支优秀的研究团队，我们将评估以下内容：(I)全球系统生物学，包括特定物种转录分析和生物信息学；HIV和SIV储存库使用新的检测方法来测量整合病毒、总病毒和可诱导病毒；免疫细胞亚群的炎症和免疫表型；全身性微生物移位和胃肠道屏障完整性；血液和胃肠道中的药物水平和动力学。我们相信，这些拟议的研究将是更好地了解与艾滋病毒储存相关的方面所不可或缺的，并可能提供一种新的治疗方法，利用滥用药物来开发艾滋病毒治愈方法。

DESCRIPTION: With 35 million HIV-infected individuals worldwide, the challenge to improve health in these individuals is vast. Antiretroviral therapy (ART) suppresses HIV replication, which prevents AIDS and reduces overall mortality; however ART does not fully restore health. Indeed, despite sustained suppression of viremia, individuals cannot discontinue ART as residual HIV persists, and virus rebound is inevitable if ART is discontinued. This residual HIV reservoir is associated with ongoing inflammation. Cannabis is a widely used drug in the United States, and derivatives of cannabis such as cannabinoids are commonly used in treatment of nausea and cachexia in severe conditions such as cancer. Several studies have demonstrated that cannabinoids have the propensity to alter immune responses and decrease inflammation in vivo. We hypothesize that cannabis use in the context of ART-treated HIV infection may decrease inflammation and the persistent HIV reservoir. Here, we provocatively propose to test this hypothesis in humans by measuring inflammation, immunity, and the HIV reservoir from blood and gastrointestinal (GI) tissues from HIV-infected individuals who report using cannabis daily compared to those reporting no drug use. Furthermore, we will assess mechanisms of cannabinoid anti- inflammatory activity ex-vivo using cannabinoid receptor agonists in co-cultures. In addition, we will exploit the non-human primate model of SIV infection to test causality of this unconventional idea, by treating ART- treated, SIV infected macaques with cannabinoids to assess the effects on SIV reservoir and inflammation. With an outstanding team of researchers, we will assess the following: (i.) Global systems biology, including species-specific transcriptional analysis and bioinformatics; (ii.) The HIV and SIV reservoir using novel assays to measure integrated, total and inducible virus; (iii.) Inflammation and immunophenotype of immune cell subsets; (iv.) Systemic microbial translocation and GI tract barrier integrity; and (v.) drug levels and kinetics in blood and GI tract. We believe these proposed studies will be integral to better understanding facets associated with the HIV reservoir and may provide a novel therapeutic approach, exploiting a drug of abuse, towards development of an HIV cure.