HIV 1 VPR INDUCES G2 CELL CYCLE ARREST AND APOPTOSIS

HIV-1基因产物是一种96个氨基酸的蛋白质， 对于病毒复制和可能是HIV-1发病机制的关键。 Vpr在细胞感染后表达， 在病毒体中。 1995年，PI是第一批描述小说的人之一， Vpr蛋白的表型，其中被表达HIV-1的HIV-1感染的细胞 Vpr阻滞在细胞周期的G2期。 他们随后 发表了由Vpr诱导的细胞周期停滞之后是细胞凋亡 被捕的细胞。 最近，他们发现， Vpr的表达诱导细胞周期阻滞，但Vpr包装成 病毒粒子能够诱导细胞周期停滞， 感染后的细胞 Vpr已被证明能增强病毒 Vpr的一个潜在功能是防止T细胞克隆形成， 因此抑制了对抗原的应答的早期步骤， 建立有效的免疫反应。因此，Vpr可以是 HIV-1疾病致病特征的关键决定因素， 进一步了解Vpr的作用机制可能有助于 开发针对Vpr的治疗剂。 辐射或化学修饰对细胞DNA的损伤可导致 在细胞周期的多个点停滞，包括所谓的G2 检查站 损伤修复失败可导致细胞凋亡。 根据PI，Vpr是已知的唯一诱导这种 在哺乳动物细胞中有效的细胞周期停滞在G2。 因此， 了解Vpr的作用机制也很重要 在理解导致细胞停滞的信号转导途径时， 在哺乳动物细胞的G2检查点。 在此之前，PI生成 大量关于Vpr作用的初步数据， 许多独特的测定用于评估Vpr功能，并开发了 这些试剂将使他能够有效地进一步推进 Vpr作用机制的研究。 具体目标是：目标1。 进一步表征HIV-1 Vpr引起的细胞周期阻滞。 目标2. 到 进一步表征Vpr介导的细胞凋亡目的3. 为了识别细胞 参与Vpr介导的细胞周期停滞和凋亡的因子。

The HIV-1 gene product is a 96 amino acid protein, which is important for viral replication and likely to be critical for HIV-1 pathogenesis. Vpr is expressed following infection of cells and is also found packaged in virions. In 1995, the PI was among the first to describe a novel phenotype of the Vpr protein whereby cells infected by HIV-1 expressing Vpr undergo arrest at the G2 phase of the cell cycle. They subsequently published that cell cycle arrest induced by Vpr is followed by apoptosis of the arrested cells. Recently, they found that not only does de novo expression of Vpr induce cell cycle arrest, but Vpr packaged into virions is capable of inducing cell cycle arrest when introduced into cells following infection. Vpr has been shown to augment virus production and one potential function of Vpr is to prevent T-cell clonal expansion in response to antigens thus suppressing an early step in establishing an effective immune response. Therefore, Vpr may be a critical determinant for pathogenic features of HIV-1 disease and further understanding of Vpr mechanisms of action may facilitate the development of therapeutic agents directed against Vpr. Damage to cell DNA by irradiation or chemical modification can lead to arrest at multiple points in the cell cycle including the so-called G2 checkpoint. Failure to repair the damage can lead to apoptosis. According to the PI, Vpr is the only gene product known to induce such an efficient cell cycle arrest in mammalian cells at G2. Thus, an understanding of the mechanism of action of Vpr will also be important in understanding the signal transduction pathways which lead to arrest at the G2 checkpoint in mammalian cells. Previously, the PI generated a considerable amount of preliminary data about Vpr action, developed a number of unique assays for assessment of Vpr function and developed reagents which will allow him to effectively carry forward further studies on the mechanism of Vpr action. The specific aims are: Aim 1. To further characterize cell cycle arrest by HIV-1 Vpr. Aim 2. To further characterize Vpr mediated apoptosis Aim 3. To identify cellular factors involved in Vpr-mediated cell cycle arrest and apoptosis.