Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy.
Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy.
复制标题
Akt 抑制剂作为 HIV-1 感染巨噬细胞特异性抗病毒疗法。
DOI：
10.1186/1742-4690-5-11
复制
发表时间：
2008-01-31
期刊：
影响因子：
3.3
通讯作者：
Kim, Baek
中科院分区：
文献类型：
--
作者：
Chugh, Pauline;Bradel-Tretheway, Birgit;Monteiro-Filho, Carlos Mr;Planelles, Vicente;Maggirwar, Sanjay B.;Dewhurst, Stephen;Kim, Baek
与CD 4 + T细胞不同，HIV-1感染的巨噬细胞即使在应激下也表现出延长的寿命，这与它们作为长寿HIV-1储库的体内作用一致。在这里，我们证明了PI 3 K/Akt抑制剂，包括临床上可用的米替福新，显着减少了HIV-1从长寿命病毒感染的巨噬细胞的生产。这些PI 3 K/Akt抑制剂使受感染的巨噬细胞对它们通常暴露于的细胞外应激超敏，并最终导致受感染的巨噬细胞的细胞死亡而不伤害未感染的细胞。基于这些Akt抑制剂的数据，我们能够进一步研究HIV-1感染如何利用PI 3 K/Akt通路来建立HIV-1感染的细胞保护作用，从而延长感染的巨噬细胞（一种关键的病毒储存库）的寿命。首先，我们发现HIV-1感染激活了原代人巨噬细胞中充分表征的促存活PI 3 K/Akt途径，如通过减少的PTEN蛋白表达和增加的Akt激酶活性所反映的。有趣的是，HIV-1或SIV达特的表达足以介导这种细胞保护作用，这种作用依赖于达特的碱性结构域，该区域先前已被证明与p53结合。接下来，我们观察到这种相互作用似乎有助于PTEN表达的下调，因为发现HIV-1达特与PTEN竞争p53结合;已知这导致p53不稳定，从而减少PTEN蛋白的产生。由于HIV-1感染的巨噬细胞显示出高度升高的Akt活性，我们的研究结果共同表明，PI 3 K/Akt抑制剂可能是一种新的治疗方法，用于干扰建立长寿的HIV-1感染的水库。
Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs. Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually lead to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat – a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production. Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.
登录
查看更多内容
影响因子：
5.6
作者：
Chugh P;Fan S;Planelles V;Maggirwar SB;Dewhurst S;Kim B
通讯作者：
Kim B
影响因子：
7.5
作者：
Bhoopat, L;Rithaporn, TS;Thorner, PS
通讯作者：
Thorner, PS
DOI：
10.1006/bbrc.2001.5626
发表时间：
2001-09-21
影响因子：
3.1
作者：
Ariumi, Y;Kaida, A;Shimotohno, K
通讯作者：
Shimotohno, K
影响因子：
4.8
作者：
Edwin, F;Singh, R;Patel, TB
通讯作者：
Patel, TB
影响因子：
3.4
作者：
Ernst, DS;Eisenhauer, E;Smylie, M
通讯作者：
Smylie, M