Investigating the Role of HIV X4 Variants in Pulmonary Vascular Remodeling and Pulmonary Hypertension in Humanized Mice

研究 HIV X4 变异体在人源化小鼠肺血管重塑和肺动脉高压中的作用

• 批准号: 9554080
• 负责人: SHARILYN ALMODOVAR
• 金额: $ 10.4万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9554080
• 关键词: Investigating; Role; HIV; X4; Variants

 DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is a life-threatening disease that is significantly more frequent in HIV-infected individuals even with antiretroviral therapy. How HIV contributes to the pathophysiology of HIV-PAH remains unknown. HIV proteins are the main suspects but the exact mechanisms whereby these proteins influence vascular remodeling are unknown. HIV proteins like Tat, Nef and gp120 likely play a role in the pathogenesis of HIV-PAH. HIV gp120 binds to either CCR5 (R5) or CXCR4 (X4) chemokine receptors after interacting with CD4. Either CCR5 or CXCR4-ligand interactions promote inflammation leading to vascular remodeling in animal models of PAH. We have preliminary evidence that HIV-infected individuals with PAH harbor significantly more CXCR4-utilizing HIV variants (X4 viruses). While CCR5 signaling leads to PAH in SIV-infected macaques, our finding of an association between X4 viruses and PAH in HIV-infected individuals lead us to focus specifically on the contribution of X4 viruses to HIV-PAH. Furthermore, we found that HIV-X4, compared to R5 gp120, induces over-expression of the vasoconstrictive arachidonate 5- lipoxygenase (ALOX-5) gene in pulmonary endothelial cells. Hence, our research has uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Whether CXCR4 signaling in the presence of HIV X4 virus leads to PAH remains elusive. We hypothesize that HIV X4 induces chronic inflammation leading to pulmonary vascular remodeling and PAH via CXCR4 signaling. We believe that, in order to advance this field, it is imperative to first validate a model for HIV-PAH and examine the impact of X4 viruses on the pulmonary vasculature. Unfortunately, other than non-human primates, there is no HIV-PAH animal model that recapitulates the natural history of this disease. To test our hypothesis, we propose to validate the state-of-the- art mice engrafted with human Bone marrow, Lymph node and Thymus (hu-BLT) as model for HIV-PAH. APPROACH: We propose to: 1) characterize pulmonary vascular remodeling and right ventricular hypertrophy in HIV-infected hu-BLT mice, and 2) examine the functional role of CXCR4 signaling in pulmonary vascular cells exposed to HIV X4 virus in vivo and in vitro. SIGNIFICANCE AND INNOVATION: These studies are significant because our model will accelerate mechanistic studies on the CXCR4 signaling pathway that may allow for convergent mechanistic explanations for other forms of PAH, e.g. idiopathic and hypoxia-induced PAH, and will help explain why HIV patients are more prone to vascular diseases affecting other end-organs like kidneys and brain. In addition, we bring the innovative theoretical concept that CXCR4-utilizing HIV plays a role in PAH and pioneer the hu-BLT mouse to gain insights into HIV-associated pulmonary vasculopathy.

 描述（由申请人提供）： 肺动脉高压（PAH）是一种危及生命的疾病，即使接受抗逆转录病毒治疗，在HIV感染者中也更常见。HIV如何促进HIV-PAH的病理生理学仍然未知。HIV蛋白是主要的嫌疑人，但这些蛋白影响血管重塑的确切机制尚不清楚。HIV蛋白如达特、Nef和gp 120可能在HIV-PAH的发病机制中起作用。HIV gp 120在与CD 4相互作用后与CCR 5（R5）或CXCR 4（X4）趋化因子受体结合。在PAH动物模型中，CCR 5或CXCR 4-配体相互作用促进炎症，导致血管重塑。我们有初步证据表明，PAH的HIV感染者携带更多的CXCR 4利用HIV变体（X4病毒）。虽然CCR 5信号传导导致SIV感染的猕猴中的PAH，但我们发现X4病毒与HIV感染个体中的PAH之间存在关联，这使我们特别关注X4病毒对HIV-PAH的贡献。此外，我们发现，HIV-X4，R5 gp 120相比，诱导过度表达的血管收缩花生四烯酸5-脂氧合酶（ALOX-5）基因在肺内皮细胞。因此，我们的研究已经发现X4病毒在HIV-PAH的病理生理学中是潜在的因子。在HIV X4病毒存在下CXCR 4信号传导是否导致PAH仍然难以捉摸。我们假设HIV X4通过CXCR 4信号转导诱导慢性炎症，导致肺血管重塑和PAH。我们认为，为了推动这一领域的发展，必须首先验证艾滋病毒-多环芳烃模型，并检查 X4病毒对肺血管的影响。不幸的是，除了非人类灵长类动物，没有HIV-PAH动物模型，重演这种疾病的自然史。为了验证我们的假设，我们建议验证移植人骨髓、淋巴结和胸腺（hu-BLT）的最先进小鼠作为HIV-PAH模型。方法：我们建议：1）表征HIV感染的hu-BLT小鼠中的肺血管重构和右心室肥大，和2）在体内和体外检查暴露于HIV X4病毒的肺血管细胞中CXCR 4信号传导的功能作用。意义和创新：这些研究意义重大，因为我们的模型将加速对CXCR 4信号通路的机制研究，这可能允许对其他形式的PAH（例如特发性和缺氧诱导的PAH）进行趋同机制解释，并将有助于解释为什么HIV患者更容易发生影响其他终末器官（如肾脏和大脑）的血管疾病。此外，我们带来了利用CXCR 4的HIV在PAH中发挥作用的创新理论概念，并开创了hu-BLT小鼠，以深入了解HIV相关的肺血管病变。