Microbial Dysbiosis and TLR2 Activation Contribute to Immune Activation, Inflammation and HIV Persistence in the Context of Opioid Abuse Despite ART Therapy

尽管接受了 ART 治疗，但在阿片类药物滥用的情况下，微生物失调和 TLR2 激活仍会导致免疫激活、炎症和 HIV 持续存在

• 批准号: 9389140
• 负责人: Sabita Roy
• 金额: $ 53.73万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389140
• 关键词: Animals; Anti-Retroviral Agents; Attenuated; Automobile Driving; Bacterial Translocation; Cells; Chronic; Combined Modality Therapy; Communities; Data; Development; Disease; Disease Progression; Drug abuse; Endotoxins; Epithelial Cells; Genes; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Health; Heroin; Homeostasis; Immune; Immune Cell Activation; Individual; Infection; Inflammation; Inflammatory; Intestines; Intravenous; Lead; Link; Measures; Microbe; Morphine; Mus; Opioid; Patients; Pharmaceutical Preparations; Play; Population; Prevalence; Probiotics; Process; Ribosomes; Role; Substance abuse problem; TLR2 gene; TLR4 gene; Testing; Therapeutic; Viral; Virulent; base; cytokine; drug abuser; gut microbiota; humanized mouse; immune activation; immune function; knockout animal; microbial; microbial community; microbiome; microbiota; mouse model; opioid abuse; prevent; restoration

Project Summary Persistent inflammation and immune activation drive HIV disease progression despite ART therapy. However, the underlying mechanisms are currently speculative and not clearly delineated. Gut leakiness and microbial translocation are hallmarks of HIV disease progression. Interestingly, chronic opioid abuse is also well documented to induce gut leakiness and sustained microbial translocation. Increasing number of studies strongly support the concept that the gut microbiota, play a significant role in maintaining gut homeostasis and gut barrier function. Although a few studies have correlated the host microbiome in HIV infected patients with gut barrier function disruption and microbial translocation, the consequence in the context of antiretroviral treatment (ART) still remains largely unexplored. There is no data on the consequences of an altered microbiome with immune activation and viral persistence in HIV patients on ART therapy in the context of opioid abuse. Although most studies measure endotoxin levels and bacterial products associated with gram- negative bacterial infection with inflammation and HIV disease progression, recent studies clearly show a distinct enrichment and prevalence of gram positive bacterial communities in HIV infected patients when compared to normal healthy individuals. Our preliminary data show significant expansion and translocation of gram positive bacterial communities in HIV infected BLT mice which are further exacerbated in the context of opioid treatment. Our central hypothesis is that microbial dysbiosis with preferential expansion of Gram positive (G+) bacterial communities in HIV infected individuals and HIV infected individuals that are opioid abusers lead to G+ bacterial translocation, TLR2/TLR4 activation and is the driving mechanism for immune cell activation and sustained inflammation contributing to disease progression and preventing the restoration of normal health in HIV-infected individuals that are opioid drug abusers. We will further investigate if treatment with ART restores homeostasis or exacerbates dysbiosis. We will test our hypothesis using NSG-BLT humanized murine model of HIV and HIV in context of substance abuse and ART. In Specific Aim 1 we will determine the role of microbial dysbiosis, expansion of gram-positive bacterial communities and gut leakiness with immune activation and viral persistence. In Specific Aim 2 we will determine that activation of TLR-2 in immune cells and gut epithelial cells results in immune activation and viral persistence following HIV infection and in the context of opioid drug abuse and ART treated humanized mice. In Specific Aim 3 we will determine that combination therapy with Probiotics and TLR2 antagonists will restore gut homeostasis and attenuate immune activation thereby delaying HIV disease progression in the context of opioid abuse and ART. The results from these studies will allow for the development of new adjunct therapeutic strategies to attenuate immune activation and delay HIV disease progression both in HIV infected patients that are on ART and in HIV infected drug abusing population.

项目摘要 持续的炎症和免疫激活驱动艾滋病毒疾病的进展，尽管ART治疗。然而，在这方面， 其基本机制目前是推测性的，没有明确界定。肠道渗漏和微生物 易位是HIV疾病进展的标志。有趣的是，慢性阿片类药物滥用也很好， 据记载可诱导肠道渗漏和持续的微生物移位。越来越多的研究 强烈支持肠道微生物群在维持肠道稳态中发挥重要作用的概念， 肠道屏障功能尽管一些研究已经将HIV感染患者的宿主微生物组与 肠道屏障功能破坏和微生物易位，在抗逆转录病毒背景下的结果 抗逆转录病毒治疗（ART）仍然在很大程度上未被探索。没有数据表明， 在抗逆转录病毒治疗背景下接受抗逆转录病毒治疗的HIV患者中具有免疫激活和病毒持久性的微生物组 阿片类药物滥用虽然大多数研究测量与革兰氏阴性菌相关的内毒素水平和细菌产物， 阴性细菌感染与炎症和艾滋病毒疾病进展，最近的研究清楚地表明， 当HIV感染患者中的革兰氏阳性细菌群落明显富集和流行时， 与正常的健康人相比。我们的初步数据显示， 感染HIV的BLT小鼠中的革兰氏阳性细菌群落，其在 阿片类药物治疗我们的中心假设是，微生物生态失调与革兰氏阳性菌的优先扩增， （G+）HIV感染者和阿片类药物滥用者中的HIV感染者的细菌群落 G+细菌易位，TLR 2/TLR 4激活，是免疫细胞激活的驱动机制 持续的炎症导致疾病进展并阻止正常健康的恢复 艾滋病毒感染者中的阿片类药物滥用者。我们将进一步研究是否用ART治疗 恢复体内平衡或加剧生态失调。我们将使用人源化的NSG-BLT来测试我们的假设。 HIV和HIV在药物滥用和ART背景下的鼠模型。在具体目标1中，我们将 确定微生物生态失调、革兰氏阳性菌群扩张和肠道渗漏的作用 免疫激活和病毒持久性。在具体目标2中，我们将确定TLR-2的激活， 免疫细胞和肠上皮细胞导致免疫激活和HIV感染后病毒持续存在 以及在阿片类药物滥用和ART治疗的人源化小鼠的情况下。在具体目标3中，我们将确定 益生菌和TLR 2拮抗剂的联合治疗将恢复肠道内稳态， 免疫激活，从而在阿片类药物滥用和ART的背景下延迟HIV疾病进展。 这些研究的结果将有助于开发新的辅助治疗策略， 在接受ART HIV感染患者和HIV患者中， 受感染的吸毒人群。