HIV Persistence and Cardiopulmonary Disease

 描述(由申请人提供)：与普通人群相比，HIV患者的肺动脉高压(PAH)增加了10倍以上。慢性炎症驱动的内皮细胞增殖限制了血流动脉，增加了右心压。在感染SHV的猕猴中也可以见到PAH，尸检发现肺血管内膜增厚证实了这一点。治疗PAH的一种新方法是使用CCR5阻断药物马拉韦罗，该药物在Shiv+动物(Kelly，et.Al，2014)。这一发现支持了一种观点，即PAH是由慢性炎症驱动的，但不能解释HIV患者PAH增加的原因。我们推测，艾滋病毒介导的T细胞耗尽和调节失调损害了控制慢性炎症的关键机制。正常情况下，T细胞向NK细胞提供共刺激作用，从而增强其杀伤树突状细胞(DC)的S细胞毒效应的效力。在缺乏正常T细胞功能的情况下，NK不能接受关键的共刺激，其清除DC的能力丧失，炎症控制也随之受损。我们治疗PAH的策略是使用两种临床批准的药物，唑来膦酸和IL-2，这两种药物共同激活和扩大共刺激的T细胞，恢复正常的T细胞功能，重建NK共刺激、DC杀伤和控制炎症的能力。由于帕金森病的高发病率和马拉韦罗的治疗效果得到证实，希沃克病毒感染的猕猴是测试新的治疗策略的理想模型，包括直接激活T细胞来化解慢性炎症。艾滋病毒疾病的多种共病情况被认为与潜在的慢性免疫激活和炎症有关。通过开发针对PAH的治疗干预措施，我们可能会确定一种通常对阻断慢性炎症有用的策略，该策略将改善和延长艾滋病毒患者的生命。

 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is increased more than 10-times in patients with HIV compared to the general population. Endothelial cell proliferation driven by chronic inflammation restricts blood flow arteries and increases right hear pressures. PAH is also seen in SHIV-infected macaques and was confirmed by necropsy findings of intimal thickening in the pulmonary vasculature. One new approach to PAH treatment uses the CCR5-blocking drug Maraviroc that was therapeutic in SHIV+ animals (Kelly, et. al, 2014). This finding supports a view that PAH is driven by chronic inflammation but does not explain the reasons for increased PAH in patients with HIV. We postulate that HIV-mediated depletion and dysregulation of T cells impairs a critical mechanism for the control of chrnic inflammation. Normally,  T cells provide costimulation to NK that increases their potency s cytotoxic effectors against dendritic cells (DC). In the absence of normal  T cell functio, NK do not receive critical costimulation, their capacity for eliminating DC is lost and with it, contrl of inflammation is impaired. Our strategy for treating PAH is to use two clinically approved drugs, zoledronic acid and IL2, that together will activate and expand the costimulatory  T cells By restoring normal  T cells function, we reconstitute the capacity for NK costimulation, DC killing and control of inflammation. Because of high PAH incidence and a proven therapeutic effect of Maraviroc, the SHIV-infected macaque is an ideal model for testing new therapeutic strategies including the direct activation of  T cells to resolve chronic inflammation. Mutiple co-morbid conditions of HIV disease are believed to be related to an underlying chronic immune activation and inflammation. By developing a therapeutic intervention against PAH, we may identify a strategy that is generally useful for blocking chronic inflammation that will improve an extend the lives of patients with HIV.