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，这一点很重要 对于病毒复制，可能是HIV-1致病的关键。 VPR在细胞感染后表达，也被发现包装在 在病毒粒子中。1995年，少年派是最早描述一部小说的人之一 HIV-1感染细胞表达VPR蛋白的表型 VPR在细胞周期的G2期发生停滞。他们随后 已发表的研究表明，VPR引起的细胞周期停滞之后是细胞凋亡 被逮捕的细胞。最近，他们发现，不仅从头开始 VPR的表达诱导细胞周期停滞，但VPR包装在 病毒粒子被引入细胞后，能够诱导细胞周期停滞 感染后的细胞。VPR已被证明可以增强病毒 VPR的一个潜在功能是阻止T细胞克隆 对抗原的反应扩张，从而抑制了早期的 建立有效的免疫反应。因此，VPR可能是一种 HIV-1疾病致病特征的关键决定因素和 进一步了解VPR的作用机制可能有助于 针对vpr的治疗药物的开发。 辐射或化学修饰对细胞DNA的损伤可导致 在细胞周期中的多个点发生停滞，包括所谓的G2 检查站。如果不能修复损伤，可能会导致细胞凋亡。 根据PI的说法，VPR是已知的唯一能引起这种情况的基因产物 哺乳动物细胞在G2期的有效细胞周期停滞。因此，一个 了解vpr的作用机制也很重要。 在理解导致停滞的信号转导通路方面 在哺乳动物细胞的G2检查点。以前，PI生成 开发了大量关于VPR行动的初步数据 开发了多种评估VPR功能的独特方法 这些试剂将使他能够有效地进一步发展 VPR作用机理的研究。具体目标是：目标1。 进一步鉴定HIV-1VPR引起的细胞周期停滞。目标2.目标 VPR介导的细胞凋亡的进一步表征目的3.鉴定细胞 参与VPR介导的细胞周期停滞和凋亡的因素。

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.