Kelly Kathleen M, Tocchetti Carlo G, Lyashkov Alexey, Tarwater Patrick M, Bedja Djahida, Graham David R, Beck Sarah E, Metcalf Pate Kelly A, Queen Suzanne E, Adams Robert J, Paolocci Nazareno, Mankowski Joseph L
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.
J Am Heart Assoc. 2014 Apr 2;3(2):e000874. doi: 10.1161/JAHA.114.000874.
Diastolic dysfunction is a highly prevalent cardiac abnormality in asymptomatic as well as ART-treated human immunodeficiency virus (HIV) patients. Although the mechanisms underlying depressed cardiac function remain obscure, diastolic dysfunction in SIV-infected rhesus macaques is highly correlated with myocardial viral load. As cardiomyocytes are not productively infected, damage may be an indirect process attributable to a combination of pro-inflammatory mediators and viral proteins.
Given the diverse roles of CCR5 in mediating recruitment of leukocytes to inflammatory sites and serving as a receptor for HIV entry into cells, we investigated the role of CCR5 in the SIV/macaque model of diastolic dysfunction. We found that in SIV-infected macaques, CCR5 inhibition dramatically impacted myocardial viral load measured by qRT-PCR and prevented diastolic dysfunction measured by echocardiography. Complementary in vitro experiments using fluorescence microscopy showed that CCR5 ligands impaired contractile function of isolated cardiomyocytes, thus identifying CCR5 signaling as a novel mediator of impaired cardiac mechanical function.
Together, these findings incriminate SIV/HIV gp120-CCR5 as well as chemokine-CCR5 interactions in HIV-associated cardiac dysfunction. These findings also have important implications for the treatment of HIV-infected individuals: in addition to antiviral properties and reduced chemokine-mediated recruitment and activation of inflammatory cells, CCR5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR5 signaling.
舒张功能障碍在无症状以及接受抗逆转录病毒治疗的人类免疫缺陷病毒（HIV）感染者中是一种非常普遍的心脏异常情况。尽管心脏功能降低的潜在机制仍不清楚，但感染猴免疫缺陷病毒（SIV）的恒河猴的舒张功能障碍与心肌病毒载量高度相关。由于心肌细胞不会被有效感染，损伤可能是由促炎介质和病毒蛋白共同作用导致的间接过程。
鉴于趋化因子受体5（CCR5）在介导白细胞募集到炎症部位以及作为HIV进入细胞的受体中具有多种作用，我们研究了CCR5在SIV/猕猴舒张功能障碍模型中的作用。我们发现，在感染SIV的猕猴中，CCR5抑制显著影响通过定量逆转录聚合酶链反应（qRT-PCR）测得的心肌病毒载量，并预防了通过超声心动图测得的舒张功能障碍。使用荧光显微镜进行的补充体外实验表明，CCR5配体损害了分离的心肌细胞的收缩功能，从而确定CCR5信号传导是心脏机械功能受损的一种新型介质。
总之，这些发现表明SIV/HIV gp120-CCR5以及趋化因子-CCR5相互作用与HIV相关的心脏功能障碍有关。这些发现对于HIV感染者的治疗也具有重要意义：除了抗病毒特性以及减少趋化因子介导的炎症细胞募集和激活外，CCR5抑制可能通过阻止心肌细胞CCR5信号传导而提供心脏保护作用。
