Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway.
Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway.
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DOI：
10.1186/1742-4690-5-19
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发表时间：
2008-02-08
期刊：
影响因子：
3.3
通讯作者：
Peralta, Liliana Martinez
中科院分区：
文献类型：
--
作者：
Larrosa, Pablo N. Fernandez;Croci, Diego O.;Riva, Diego A.;Bibini, Mariel;Luzzi, Renata;Saracco, Monica;Mersich, Susana E.;Rabinovich, Gabriel A.;Peralta, Liliana Martinez
HIV引发了CD4+T细胞的下降，导致细胞免疫功能的进行性功能障碍。虽然艾滋病毒感染的急性期对细胞死亡的易感性增加，但持续感染的巨噬细胞和静止的T细胞似乎对细胞死亡具有抵抗力，这是病毒产生的潜在储备库。用过氧化氢(H_2O_2)和星形孢子素(STS)处理淋巴系(H9/HTLVIIIB和J1.1)和单核细胞(U1)前单核细胞(U1)HIV-1持续感染细胞株24 h，检测其对细胞凋亡的敏感性，并与未感染细胞系(分别为H9、Jurkat和U937)进行比较。当暴露在不同的促凋亡刺激下时，与未感染的细胞相比，所有持续感染的细胞株的凋亡细胞频率都显著降低。这种影响与病毒复制的大小无关，因为暴露于肿瘤坏死因子-α或聚甲基丙烯酸甲酯诱导的淋巴细胞或前单核细胞中的病毒产生并不显著改变它们对过氧化氢或STS诱导的细胞死亡的敏感性。机制分析表明，未感染和持续感染的细胞在线粒体膜电位和caspase-3激活方面存在显著差异。此外，Western印迹分析显示，经过氧化氢或STS处理的持续感染细胞的线粒体中促凋亡的Bax水平显著降低，但在未感染的细胞中未见明显下降。这项研究首次证明，在持续感染的淋巴和单核细胞中，对凋亡的抵抗独立于活跃的病毒生产，并涉及线粒体途径的调节。了解这一效应对于特别针对病毒库的持久性至关重要，并为未来的治疗策略提供见解，以促进彻底根除病毒。
HIV triggers the decline of CD4+ T cells and leads to progressive dysfunction of cell-mediated immunity. Although an increased susceptibility to cell death occurs during the acute phase of HIV infection, persistently-infected macrophages and quiescent T-cells seem to be resistant to cell death, representing a potential reservoir for virus production. Lymphoid (H9/HTLVIIIB and J1.1) and pro-monocytic (U1) HIV-1 persistently-infected cell lines were treated with hydrogen peroxide (H2O2) and staurosporine (STS) for 24 h, and susceptibility to apoptosis was evaluated and compared with uninfected counterparts (H9, Jurkat and U937 respectively). When exposed to different pro-apoptotic stimuli, all persistently-infected cell lines showed a dramatic reduction in the frequency of apoptotic cells in comparison with uninfected cells. This effect was independent of the magnitude of viral replication, since the induction of viral production in lymphoid or pro-monocytic cells by exposure to TNF-α or PMA did not significantly change their susceptibility to H2O2- or STS-induced cell death. A mechanistic analysis revealed significant diferences in mitochondrial membrane potential (MMP) and caspase-3 activation between uninfected and persistently-infected cells. In addition, Western blot assays showed a dramatic reduction of the levels of pro-apototic Bax in mitochondria of persistently-infected cells treated with H2O2 or STS, but not in uninfected cells. This study represents the first evidence showing that resistance to apoptosis in persistently-infected lymphoid and monocytic cells is independent of active viral production and involves modulation of the mitochondrial pathway. Understanding this effect is critical to specifically target the persistence of viral reservoirs, and provide insights for future therapeutic strategies in order to promote complete viral eradication.
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