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

大麻对治疗 HIV/SIV 的炎症和病毒持久性的影响

• 批准号: 9004614
• 负责人: Nichole Rose Klatt
• 金额: $ 88.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9004614
• 关键词: Acquired Immunodeficiency Syndrome; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Bioinformatics; Biological Assay; Blood; Cachexia; Cannabinoids; Cannabis; Cells; Coculture Techniques; Development; Drug usage; Etiology; Gastrointestinal tract structure; HIV; HIV Infections; Health; Human; Immune; Immune response; Immunity; Immunophenotyping; Individual; Infection; Inflammation; Kinetics; Macaca; Malignant Neoplasms; Measures; Modeling; Morbidity - disease rate; Nausea; Pharmaceutical Preparations; Property; Reporting; Research Personnel; Residual state; SIV; Systems Biology; Testing; Tissues; United States; Viral; Viremia; Virus; antiretroviral therapy; cannabinoid receptor; cannabinoid treatment; drug of abuse; gastrointestinal; improved; in vivo; marijuana use; microbial; mortality; nonhuman primate; novel; novel therapeutic intervention; prevent; translational approach

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.

全球有3500万艾滋病毒感染者，改善这些人的健康面临巨大挑战。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并不能完全恢复健康。事实上，尽管持续抑制病毒血症，个体不能停止抗逆转录病毒治疗，因为残留的艾滋病毒仍然存在，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储存库与持续的炎症有关。大麻在美国是一种广泛使用的药物，大麻的衍生物如大麻素通常用于治疗癌症等严重疾病中的恶心和恶病质。几项研究表明，大麻素具有改变免疫反应和减少体内炎症的倾向。我们假设在ART治疗的HIV感染的背景下使用大麻可能会减少炎症和持续的HIV储存库。在这里，我们建议通过测量炎症，免疫力和HIV感染者的血液和胃肠道（GI）组织中的HIV储库来测试人类中的这一假设，这些HIV感染者报告每天使用大麻，与那些报告没有药物使用的人相比。此外，我们将在共培养物中使用大麻素受体激动剂评估大麻素抗炎活性的离体机制。此外，我们将利用SIV感染的非人灵长类动物模型来测试这种非常规想法的因果关系，通过用大麻素处理ART处理的SIV感染的猕猴来评估对SIV储库和炎症的影响。我们将通过一个优秀的研究团队，评估以下内容：（i）全球系统生物学，包括物种特异性转录分析和生物信息学; HIV和SIV储库使用新的测定来测量整合的、全部的和可诱导的病毒;（iii.）炎症和免疫细胞亚群的免疫表型;（iv.）全身微生物移位和胃肠道屏障完整性;和（v.）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不可或缺的，以更好地了解与艾滋病毒水库相关的方面，并可能提供一种新的治疗方法，利用滥用药物，对艾滋病毒治疗的发展。