Repairing the intestinal epithelium from the dual action of HIV and drug use

产品说明：在有效的抗逆转录病毒治疗的时代，接受治疗的艾滋病毒感染的成年人患非艾滋病相关疾病的风险更大，这些疾病包括心血管疾病、神经认知疾病、骨质疏松症、肝病、肾病和某些癌症。导致非艾滋病并发症风险的因素包括抗逆转录病毒药物毒性、传统风险因素（如药物滥用、肥胖和高血压）的高患病率以及免疫功能障碍和炎症。事实上，非法药物使用仍然是全国艾滋病病例中暴露于艾滋病毒的第二大最常见方式，占总诊断的31%。除了吸毒是初次接触艾滋病毒的一个因素外，持续吸毒、与吸毒有关的生活方式的相关因素、缺乏获得和坚持吸毒和艾滋病毒感染治疗的机会，都是加剧疾病进展的相关因素。特别地，胃肠道及其导致的屏障功能丧失是急性HIV感染和药物滥用的主要目标，导致继发于炎症的缺血性病变的发生。因此，艾滋病毒感染和药物使用之间的负面协同作用影响肠道通透性是这个建议的核心。目前，HIV感染人群的治疗重点是（i）改进的抗逆转录病毒化合物，（ii）针对潜伏病毒库的基于“治愈”的策略，以及（iii）针对全身免疫激活和高凝状态的抗炎、益生菌、抗生素和抗凝治疗。这项申请概述了一个完全不同的分子和细胞的艾滋病毒治疗目标-修复肠道屏障缺陷。我们的理由是，HIV和非法药物介导的肠粘膜破裂导致慢性暴露于易位的微生物产物，从而驱动全身炎症。炎症和凝血生物标志物的这些细微升高与HIV全因发病率和死亡率风险的显著和持续增加相关。因此，我们提出了一个创新的三层研究战略，以改变艾滋病毒科学界的谈话，通过增加肠道损伤由于艾滋病毒感染和使用非法药物的联合侮辱。(i)我们将在体外确定粘膜T细胞耗竭的分子和细胞机制，伴随着IL-17和IL-22产生的优先减少，抗逆转录病毒药物毒性，形态发生模式，（通过Wnt、Notch和hedgehog途径），肠细胞凋亡，和固有层纤维化（由于HIV感染）和肠缺血性损伤（由于药物使用）结合联合收割机通过上皮完整性和稳态的损失增加肠通透性（IP）。(ii)在SIV灵长类动物模型中进行体内研究，我们将直接测试外源性IL-17和IL-22降低肠道通透性、减少全身炎症并可能改变疾病进程的能力。最后，（iii）我们将通过启动一项以人生长激素（hGH）为治疗药物的试点临床研究，并以肠道通透性降低、循环微生物产物减少以及高凝状态和炎症生物标志物减少为临床终点，来检验我们的假设，即关注上皮修复是治疗HIV和非法药物促进的粘膜损伤的一种变革性方法。我们希望建立一个新的范例，我们期望确定新的治疗策略来治愈破裂的上皮，随后阻止微生物产物的易位，最大限度地减少全身炎症，并治疗HIV感染的吸毒者。

DESCRIPTION: In the era of effective antiretroviral therapy, treated HIV-infected adults have a greater risk of non-AIDS related morbidity, which includes cardiovascular disease, neurocognitive disease, osteoporosis, liver disease, kidney disease, and some cancers. Among the factors that contribute to the risk of non-AIDS complications are antiretroviral drug toxicity,a high prevalence of traditional risk factors (such as substance abuse, obesity, and hypertension), and immune dysfunction and inflammation. In fact, illicit drug use remains the second most common mode of exposure to HIV among AIDS cases nationwide, representing 31% of total diagnoses. In addition to drug use as a factor in initial exposure to HIV, ongoing drug use, correlates of the lifestyles associated with drug use, and lack of access and adherence to treatments for drug use and HIV infection are among the related factors that exacerbate disease progression. In particular, the gastrointestinal tract and its resultant loss of barrier function i a major target for acute HIV infection and drugs of abuse, leading to the occurrence of ischemic lesions secondary to inflammation. Thus, negative synergy between HIV infection and drug use impacting intestinal permeability is central to this proposal. Currently the therapeutic focus for the HIV-infected population is on (i) improved antiretroviral compounds, (ii) "cure"-based strategies directed at the latent viral reservoir, and (iii) anti-inflammatory, probiotic, antibiotc, and anti-coagulation treatments that target systemic immune activation and hypercoagulability. This application outlines an entirely distinct molecular and cellular target for HIV treatment - repairing the intestinal barrier defect. We reason that HIV- and illicit drug-mediated breakdown in the intestinal mucosa leads to chronic exposure to translocated microbial products, which drive systemic inflammation. These subtle elevations in both inflammatory and coagulation biomarkers are associated with dramatic and sustained increases in risk of all-cause morbidity and mortality in HIV. We therefore propose an innovative three-tiered research strategy to alter the conversation in the HIV scientific community, informed by the augmentation in intestinal damage due to the joint insult of HIV infection and use of illicit drugs. (i) We will define in vito the molecular and cellular mechanisms by which mucosal T cell depletion, accompanied by the preferential decrease in IL-17 and IL-22 production, antiretroviral drug toxicity, morphogenetic patterning (by the Wnt, Notch, and hedgehog pathways), enterocyte apoptosis, and lamina propria fibrosis (due to HIV infection) and intestinal ischemic damage (due to drug use) combine to increase intestinal permeability (IP) via a loss in epithelial integrity and homeostasis. (ii) Working in vivo in the SIV primate model, we will test directly the ability of exogenous IL-17 and IL-22 to decrease intestinal permeability, reduce systemic inflammation, and possibly alter the disease course. Finally, (iii) we will test our hypothesis that focusing on epithelial repair is a transformative approach to HIV- and illicit drug-promoted mucosal damage, by initiating a pilot clinical study with human Growth Hormone (hGH) as the therapeutic and a reduction of intestinal permeability, a decline in circulating microbial products, and a decrease in biomarkers of hypercoagulability and inflammation, as the clinical endpoints. We hope to establish a new paradigm in which we expect to identify novel therapeutic strategies to heal the breached epithelium, and subsequently stem the translocation of microbial products, minimize systemic inflammation, and treat the HIV-infected drug user.