HIV and Cocaine Drive Bone-Marrow Blood (BMB) Barrier Dysfunction and Altered Hematopoietic Stem Cell (HSC) Differentiation Leading to Cardiovascular Disease

艾滋病毒感染者（PLWH），即使接受抗逆转录病毒治疗（ART）， 非艾滋病相关疾病的发作，如心血管疾病（CVD）的过早发展。在 事实上，在美国，CVD已经成为PLWH中非AIDS相关死亡的第二大常见原因。 在此，我们的目标是破译HIV相关CVD的潜在机制。具体来说，我们的重点是 骨髓-血液（BMB）屏障和干细胞生态位，作为一个脆弱的微环境，调节 CVD免疫状态。骨髓（BM）是造血干细胞（HSC）的重要储存库， 其产生免疫细胞，包括循环单核细胞（炎性对非炎性）。最近 研究强调了血管系统渗透性（或缺乏其）在控制HSC中的重要性 分化此外，BM小生境中负责维持长期的血管系统区域， HSC表现出类似于血脑的限制性渗透性特性（由周细胞调节） 屏障虽然艾滋病毒感染在抗逆转录病毒治疗时代对骨髓的影响尚不清楚，但它可能反映了观察到的情况。 在大脑中。值得注意的是，众所周知，艾滋病毒感染和炎症在大脑中导致减少 周细胞覆盖和增加的血管通透性。流行病学研究表明， 物质使用障碍在PLWH中很常见。此外，药物滥用在《公约》中有详细记载。 加剧了艾滋病的病理学。例如，长期使用可卡因独立地增加CVD风险， 增强其在PLWH中的发展，突出了HIV感染和可卡因使用之间的协同联系。我们 提出，由于HIV感染，BM血管破坏增加，周细胞覆盖减少， 可卡因可以改变HSC分化的平衡，并驱动潜在的慢性免疫激活 从而促进心血管疾病的发展因此，我们的假设是，艾滋病毒和可卡因诱导BMB屏障 使HSC偏向分化和产生炎性单核细胞的功能障碍， 促进早期CVD。功能失调的BM微环境的研究从未被作为一个因素进行过研究 在HIV感染/吸毒期间发生CVD。我们的方法在概念和技术上都具有高度创新性， 将是第一个研究BMB屏障变化的人。这一假设将使用组织清除来检验， microCT和先进的成像技术，以绘制人源化HIV感染者的3D血管结构 小鼠最后，我们建议开发一种新的人体BM血管三维组织工程模型， 研究HIV发病机制。简而言之，慢性免疫激活被认为是导致早期 HIV+/慢性可卡因使用者的CVD;然而，根本原因仍然未知。因此，识别 免疫激活机制可能导致对HIV+患者/吸毒者的靶向治疗， 管理策略，以减缓或防止斑块的发展。这些研究都属于 Avenir DP 2计划鼓励早期研究人员以创新方法追求大胆的想法。

People living with HIV (PLWH), even with anti-retroviral therapy (ART), have an accelerated and augmented onset of non-AIDS related diseases such as the premature development of cardiovascular disease (CVD). In fact, CVD has become the second most common cause of non-AIDS related mortality in PLWH in the US. Herein, we aim to decipher the underlying mechanism for HIV-associated CVD. Specifically, our focus is on the bone marrow-blood (BMB) barrier and stem cell niche, as a vulnerable microenvironment that regulates the immune status in CVD. The bone marrow (BM) is an important reservoir for hematopoietic stem cells (HSCs), which give rise to immune cells including circulatory monocytes (inflammatory vs non-inflammatory). Recent studies have highlighted the importance of vasculature permeability (or lack thereof) in controlling HSC differentiation. Additionally, areas of the vasculature in the BM niches responsible for maintaining the long-term HSCs exhibit restrictive permeability properties (regulated by pericytes) similar to that of the blood-brain barrier. While the effect of HIV infection in the BM in the era of ART is unknown, it may mirror what is observed in the brain. Of note, it is well established that HIV infection and inflammation in the brain leads to reduced pericyte coverage and increased vascular permeability. Epidemiological studies indicate that comorbid substance use disorder is common in PLWH. Furthermore, drugs of abuse are well documented in exacerbating HIV pathology. For example, chronic cocaine use independently increases CVD risk and further augments its development in PLWH, highlighting a synergistic link between HIV infection and cocaine use. We propose that increased BM vascular disruption and reduced pericyte coverage resulting from HIV infection and cocaine could alter the balance of HSC differentiation and drive the underlying chronic immune activation which advances CVD progression. Thus, our hypothesis is that HIV and cocaine induce BMB barrier dysfunction which skews HSCs towards differentiation and production of inflammatory monocytes that promote early CVD. The study of dysfunctional BM microenvironments has never been examined as a factor in CVD during HIV infection/drug use. Our approach is highly conceptually and technically innovative and would be the first to study changes in the BMB barrier. This hypothesis will be examined using tissue clearing, microCT and advanced imaging techniques to map the 3D vascular architecture in humanized HIV-infected mice. Finally, we propose to develop a new human 3D tissue engineered model of the BM vasculature for the study of HIV pathogenesis. In brief, chronic immune activation is considered the leading factor driving early CVD in HIV+/chronic cocaine users; however, the underlying cause remains unknown. Therefore, identifying the mechanism of immune activation could lead to targeted treatment of HIV+ patients/drug users and management strategies to slow or prevent plaque development. These studies fit within the framework of the Avenir DP2 program to encourage early-stage investigators to pursue bold ideas with innovative approaches.