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人类免疫缺陷病毒1型辅助蛋白Vpr:艾滋病相关胰岛素抵抗/脂肪代谢障碍综合征的致病因素?

Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?

作者信息

Kino Tomoshige, Chrousos George P

机构信息

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1583, USA.

出版信息

Ann N Y Acad Sci. 2004 Jun;1024:153-67. doi: 10.1196/annals.1321.013.

Abstract

Recent advances in the development of three different types of antiviral drugs, the nucleotide and non-nucleotide analogues acting as reverse transcriptase inhibitors (NRTIs) and the nonpeptidic viral protease inhibitors (PI), and their introduction in the management of patients with AIDS, either alone or in combination, have dramatically improved the clinical course of the disease and prolonged life expectancy in patients with AIDS. The increase in life expectancy in association with the long-term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS-related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV-1 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV-1 preintegration complex, nucleo-cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2/M phase of the cell cycle by interacting with novel 14-3-3 proteins. Vpr facilitates the interaction of 14-3-3 and its partner protein Cdc25C, which is critical for the transition of G2/M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14-3-3 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS-related insulin resistance/lipodystrophy syndrome.

摘要

三种不同类型抗病毒药物的研发取得了新进展,即作为逆转录酶抑制剂的核苷酸类似物和非核苷酸类似物(NRTIs)以及非肽类病毒蛋白酶抑制剂(PI),它们单独或联合应用于艾滋病患者的治疗,显著改善了该病的临床病程,延长了艾滋病患者的预期寿命。然而,与长期使用上述抗病毒药物相关的预期寿命增加也产生了新的发病情况和并发症。其中最主要的是相当常见的艾滋病相关胰岛素抵抗和脂肪代谢障碍综合征,其特征为显著的表型和明显的代谢紊乱。为了探寻这一特殊综合征的病理原因,我们聚焦于HIV-1辅助蛋白之一的Vpr,它具有多种功能,如病毒体整合、HIV-1整合前复合物的核转位、核质穿梭、转录激活以及诱导细胞凋亡。Vpr还可能像一种激素一样,分泌到细胞外空间并影响远处器官的功能。Vpr作为糖皮质激素受体的共激活因子,增强糖皮质激素的作用,从而诱导组织糖皮质激素超敏反应。Vpr还通过与新的14-3-3蛋白相互作用,使宿主细胞停滞在细胞周期的G2/M期。Vpr促进14-3-3与其伴侣蛋白Cdc25C的相互作用,这对细胞周期中G2/M检查点的转换至关重要,并通过将其隔离到细胞质中来抑制其活性。同样的Vpr蛋白还抑制14-3-3与其他伴侣分子即Foxo转录因子的结合。由于Foxo蛋白作为胰岛素的负转录因子发挥作用,Vpr可能导致组织对胰岛素产生抵抗。通过Vpr的这两种新发现的功能,即糖皮质激素受体活性的共激活以及对胰岛素作用于Foxo蛋白的抑制,Vpr可能参与了艾滋病相关胰岛素抵抗/脂肪代谢障碍综合征的发生发展。

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