HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer.
HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer.
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DOI：
10.1371/journal.pone.0110930
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Khati M
中科院分区：
文献类型：
--
作者：
Lopes de Campos WR;Chirwa N;London G;Rotherham LS;Morris L;Mayosi BM;Khati M
艾滋病毒相关性心肌病(HIVCM)在发展中国家引起临床关注，因为艾滋病毒-1的高流行率，特别是C亚型，以及获得高效抗逆转录病毒疗法(HAART)的机会有限。因此，我们研究了HIV-1 C亚型感染对培养的人心肌细胞的直接和间接影响，以及导致心肌细胞损伤的机制，以及减轻这种损伤的方法。我们评估了一种使用先前报道的gp120结合和HIV-1中和适配子UCLA1来缓解HIVCM的新方法。我们通过用无细胞HIV-1感染人心肌细胞或与HIV感染的单核细胞来源的巨噬细胞(MDM)共同培养人心肌细胞，建立了基于细胞的HIVCM模型。我们发现HIV-1 C亚型对心肌细胞的感染是无效的(即逆转录后其生命周期被阻断)。此外，我们发现HIV-1通过激活caspase-9启动心肌细胞的凋亡，优先通过固有的或线粒体启动的途径。使用CXCR4受体的病毒比使用变异体的CCR5更能诱导细胞凋亡。重要的是，我们发现UCLA1可减轻HIV-1诱导的心肌细胞凋亡。然而，当HIV感染的MDM触发细胞凋亡时，UCLA1对心肌细胞没有保护作用。在MDM感染前用UCLA1处理HIV-1，不能诱导心肌细胞凋亡。这些数据表明，HIV-1引起线粒体启动的细胞凋亡级联反应，通过caspase-9传递信号，而HIV-1感染的MDM主要通过caspase-8介导的死亡受体途径引起细胞凋亡。此外，这些数据表明，UCLA1通过直接与HIV-1结合和间接通过预防MDM感染来保护心肌细胞免受caspase介导的凋亡。
HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.
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影响因子：
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作者：
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通讯作者：
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Khati, Makobetsa
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作者：
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