HIV INDUCED ALTERATIONS IN CATION TRANSPORT

HIV 引起的阳离子运输改变

• 批准号: 2457797
• 负责人: JENS J KORT
• 金额: $ 10.96万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2457797
• 关键词: HIV infections; apoptosis; astrocytes; cations; cellular pathology; flow cytometry; fluorescence spectrometry; helper T lymphocyte; host organism interaction; human immunodeficiency virus; human tissue; ion transport; leukocyte activation /transformation; membrane permeability; nervous system infection; neurons; tissue /cell culture; virus protein; voltage /patch clamp

The objective of this project is to elucidate mechanisms by which the human immunodeficiency virus (HIV) induces changes in ion transport across the plasma membrane, and the effect of those changes on cell function and cytopathology in CD4+ lymphocytes, neurons and astroglial cells. Our specific aims are designed to show that first, HIV proteins NEF gp41 and gp120 alter cation transport across the plasma membrane by specific interaction with ion transport systems, or function as cation channels once inserted into the host plasma membrane. Second, the HIV- induced changes in cation plasma membrane transport lead to impairment of specific functions of the different cell types by the same mechanism. Thus, dysfunctions of neurons and astrocytes involved in the AIDS encephalopathy can be caused without viral infection of those cells via import of viral proteins into the CNS. Infection by many different lytic viruses, including HIV lead to a change in intracellular monovalent cations via changes in the activity of cation transport systems or changes in membrane permeability. In picornavirus and alphavirus infection, these cation alterations cause a number of events favoring virus replication and virus production in infected cells, and also lead to termination of host cell protein synthesis and cytopathology. Our preliminary results suggest that HIV-derived proteins/peptides alter IL-2 production by CD4+ lymphocytes due to selective inhibition of plasma membrane K+ channels. We have evidence that HIV encodes proteins with structural similarity to (i) scorpion toxins,, i.e., NEF, and gp120, and (ii), the HIV TM protein (gp41) has a similar structure to pore forming subunits of Na+ and K+ channels. Thus, like scorpion toxins, NEF and gp120 peptides may modulate existing Na+ and K+ channel activity or, new cation pores may be formed by gp41 peptides in the host cell plasma membrane. An increase in the activity of the Na+, K+-ATPase in HIV- infected CD4+ lymphocytes is consistent with an HIV-induced increase in the intracellular Na+ concentration. Thus, modulation of cation transport by such HIV proteins/peptides in astrocytes and neurons may be one key to the pathogenesis of AIDS encephalopathy. The intended investigations rationalize alterations in ion transport as a mechanism of action by which HIV proteins cause cytopathology responsible for both immunodeficiency and neurological abnormalities in HIV infection. This proposal provides new insight into the pathogenesis of AIDS and may foster development of new therapeutic approaches including modulation of specific cation transport systems.

该项目的目标是阐明机制 人类免疫缺陷病毒（HIV）引起离子转运的变化 穿过质膜，以及这些变化对细胞的影响 CD4+淋巴细胞、神经元和星形胶质细胞的功能和细胞病理学 细胞。 我们的具体目标旨在表明，首先，HIV 蛋白 NEF gp41 和 gp120 通过以下方式改变阳离子跨质膜的运输 与离子传输系统的特定相互作用，或作为阳离子发挥作用 通道一旦插入宿主质膜。 其次，艾滋病毒—— 阳离子质膜转运的诱导变化导致损伤 通过相同的机制来控制不同细胞类型的特定功能。 因此，与艾滋病有关的神经元和星形胶质细胞的功能障碍 脑病可以在这些细胞没有病毒感染的情况下引起 将病毒蛋白输入中枢神经系统。 许多不同的裂解物感染 包括 HIV 在内的病毒会导致细胞内单价的变化 通过改变阳离子传输系统的活性或 膜渗透性的变化。 在小核糖核酸病毒和甲病毒中 感染时，这些阳离子变化会导致许多有利于 受感染细胞中的病毒复制和病毒产生，也导致 终止宿主细胞蛋白质合成和细胞病理学。 我们的 初步结果表明 HIV 衍生的蛋白质/肽会改变 IL-2 由于选择性抑制血浆而产生 CD4+ 淋巴细胞 膜 K+ 通道。 我们有证据表明 HIV 编码蛋白质 与 (i) 蝎子毒素（即 NEF 和 gp120）结构相似，以及 (ii)、HIV TM蛋白(gp41)具有与成孔相似的结构 Na+ 和 K+ 通道的亚基。 因此，像蝎子毒素一样，NEF 和 gp120 肽可以调节现有的 Na+ 和 K+ 通道活性，或者新的 阳离子孔可能由宿主细胞血浆中的 gp41 肽形成 膜。 HIV 中 Na+、K+-ATP 酶的活性增加 受感染的 CD4+ 淋巴细胞与 HIV 诱导的 CD4+ 淋巴细胞增加一致 细胞内Na+浓度。 因此，阳离子的调节 这种 HIV 蛋白/肽在星形胶质细胞和神经元中的转运可能是 艾滋病脑病发病机制的关键之一。 预期的 研究将离子传输的改变合理化为一种机制 HIV 蛋白引起细胞病理学的作用 HIV感染中的免疫缺陷和神经系统异常。 这 该提案为艾滋病的发病机制提供了新的见解，并可能 促进新治疗方法的开发，包括调节 特定的阳离子传输系统。