HIV INDUCED ALTERATIONS IN CATION TRANSPORT

本项目的目标是阐明 人类免疫缺陷病毒（HIV）诱导离子转运的变化 以及这些变化对细胞的影响 CD 4+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 我们的具体目标是表明，首先，艾滋病毒蛋白质 NEF gp 41和gp 120通过以下方式改变阳离子跨质膜转运： 与离子转运系统的特异性相互作用，或作为阳离子发挥作用 通道一旦插入宿主质膜。 第二，艾滋病-- 诱导的阳离子质膜转运变化导致损伤 不同细胞类型的特定功能通过相同的机制。 因此，神经元和星形胶质细胞的功能障碍与艾滋病有关， 在没有病毒感染这些细胞的情况下， 将病毒蛋白输入CNS。 感染由许多不同的溶解 包括HIV在内的病毒导致细胞内单价 通过阳离子转运系统活性的变化， 膜通透性的变化。 在小核糖核酸病毒和甲病毒中 感染时，这些阳离子改变会导致许多有利于 病毒复制和病毒生产在受感染的细胞，也导致 终止宿主细胞蛋白质合成和细胞病理学。 我们 初步结果表明HIV衍生蛋白/肽改变IL-2 由于选择性抑制血浆，CD 4+淋巴细胞产生 膜K+通道。 我们有证据表明艾滋病毒编码的蛋白质 与（i）蝎毒素，即，NEF和gp 120，以及 (ii)HIV TM蛋白（gp 41）具有与孔形成相似的结构， Na+和K+通道的亚基。 因此，像蝎子毒素一样，NEF和 gp 120肽可以调节现有的Na+和K+通道活性，或新的 宿主细胞血浆中的GP 41肽可形成阳离子孔 膜的 HIV-1细胞Na ~+，K ~+-ATP酶活性增高， 感染的CD 4+淋巴细胞与HIV诱导的 细胞内Na+浓度。 因此，阳离子的调节 通过这种HIV蛋白/肽在星形胶质细胞和神经元中的转运， 艾滋病脑病发病的关键之一。 预期 研究使离子转运的改变合理化， HIV蛋白引起细胞病理学的作用， 免疫缺陷和神经系统异常的HIV感染。 这 该提案为艾滋病的发病机制提供了新的见解， 促进新治疗方法的开发，包括调节 特定的阳离子运输系统。

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.