Olivetta Eleonora, Federico Maurizio
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
Exp Cell Res. 2006 Apr 1;312(6):890-900. doi: 10.1016/j.yexcr.2005.12.003. Epub 2006 Jan 27.
HIV-1 Nef is the regulatory protein expressed earliest and most abundantly in the infection cycle. Its expression has been correlated with a plethora of effects detectable either in producer, target, and bystander cells, as well as in the viral particles. Even if the relationship between Nef expression and apoptosis has been already matter of investigation in infected lymphocytes, whose resistance to HIV infection is however limited to few days, this remains to be investigated in cells that in vivo well resist the HIV cytopathic effect. In such an instance, we were interested in establishing whether Nef influences the apoptotic processes in primary human-monocyte-derived macrophages (MDM). High efficiency HIV-1 infection of MDM allowed us to establish that virus-expressed Nef strongly counteracts the HIV-1-induced apoptosis. The Nef mutant analysis suggested that this effect relies on the interaction with different protein partners and cell compartments. We also observed that the Nef protection to the HIV-1-induced apoptosis correlated with the hyper-phosphorylation and consequent inactivation of the pro-apoptotic Bad protein. On the basis of these results, we propose the Nef anti-apoptotic effect as a relevant part of the mechanism of the in vivo establishment of the HIV macrophage reservoirs.
HIV-1 Nef是在感染周期中最早且表达最为丰富的调节蛋白。其表达与在病毒产生细胞、靶细胞、旁观者细胞以及病毒颗粒中可检测到的大量效应相关。尽管Nef表达与凋亡之间的关系已在受感染淋巴细胞中成为研究对象，然而这些淋巴细胞对HIV感染的抗性仅持续数天，在体内能很好抵抗HIV细胞病变效应的细胞中，这一关系仍有待研究。在此情形下，我们感兴趣于确定Nef是否影响原代人单核细胞衍生巨噬细胞（MDM）中的凋亡过程。MDM的高效HIV-1感染使我们得以确定，病毒表达的Nef强烈对抗HIV-1诱导的凋亡。Nef突变体分析表明，这种效应依赖于与不同蛋白质伙伴及细胞区室的相互作用。我们还观察到，Nef对HIV-1诱导凋亡的保护作用与促凋亡Bad蛋白的过度磷酸化及随后的失活相关。基于这些结果，我们提出Nef的抗凋亡效应是HIV巨噬细胞储存库在体内建立机制的一个相关部分。
