HIV INDUCED ALTERATIONS IN CATION TRANSPORT

这个项目的目标是阐明 人类免疫缺陷病毒(HIV)引起离子转运改变 穿过质膜，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。我们的特定目标旨在表明，第一，艾滋病毒蛋白质 NEF gp41和gp120通过改变阳离子跨质膜转运 与离子转运系统的特定相互作用，或作为阳离子起作用 通道一旦插入宿主质膜。第二，艾滋病毒-- 阳离子质膜转运的诱导改变导致损伤 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 脑病可以在这些细胞没有病毒感染的情况下通过 将病毒蛋白输入中枢神经系统。感染多种不同的溶血剂 包括HIV在内的病毒导致细胞内单价改变 通过阳离子转运系统活性的变化或 膜通透性的变化。在小核糖核酸病毒和甲型病毒中 感染，这些阳离子改变会导致一系列有利于 病毒在受感染细胞中的复制和产生，以及铅 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/肽可以改变IL-2 血浆选择性抑制引起的CD4+淋巴细胞的产生 膜K+通道。我们有证据表明HIV编码的蛋白质与 结构上与(I)蝎子毒素，即NEF和gp120相似，以及 (Ii)，HIV TM蛋白(Gp41)具有类似于成孔的结构 Na+和K+通道的亚基。因此，像蝎子毒素一样，NEF和 Gp120多肽可能调节现有的Na+和K+通道活性，或者，新的 宿主细胞质中的gp41多肽可能形成阳离子孔道。 薄膜。HIV感染者体内Na~+，K~+-ATPase活性升高 感染的CD4+淋巴细胞与HIV诱导的 细胞内Na+浓度。因此，阳离子的调制 这种HIV蛋白/肽在星形胶质细胞和神经元中的转运可能是 其中一个关键是艾滋病脑病的发病机制。目标客户 研究合理地将离子传输的改变作为一种机制 HIV蛋白引起的细胞病理学对两者的作用 HIV感染中的免疫缺陷和神经异常。这 该提案为艾滋病的发病机制提供了新的见解，并可能 促进新治疗方法的发展，包括调节 特定的阳离子传输系统。

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.