HIV Induced Cellular Pathology

描述（由申请人提供）：此处提出的工作具有为艾滋病患者的治疗做出贡献的长期目标。我们相信，如果我们对艾滋病毒生长的分子生物学有足够深入的了解，我们将发现抗逆转录病毒治疗的新目标。该项目的具体目标是：1)了解NF-kappaB转录因子与其在HIV基因组和细胞基因中的结合位点的相互作用；2)了解RelB是否在HIV基因组转录中起负向作用；3)鉴定并克隆使T细胞成为艾滋病毒生长的肥沃土壤的蛋白质基因。该建议源于对NF-kappaB是HIV基因组表达的关键转录因子的理解。对于Aim 1，我们将使用我们最近开发的新技术来准确确定NF-kappaB蛋白家族的哪些成分负责该因子的活性。我们还将把这项工作扩展到研究当T细胞从静止状态到活跃状态（从抵抗HIV到允许病毒生长的过渡）时激活的细胞基因。我们不仅希望了解所涉及的蛋白质，还希望了解为什么不同的基因使用微妙的不同结合位点，以及为什么NF-kappaB激活的不同刺激可能导致对单个DNA位点的不同蛋白质需求。Aim 2源于我们最近的一项研究，即组成NF-kappaB的Rel相关亚基之一RelB在调控中起负作用。它可以建立激活阈值以及下调对NF-kappaB有反应的基因的转录。对于Aim 3，我们将尝试寻找新的蛋白质，这些蛋白质在导致HIV容许性激活和伴随的潜伏HIV基因组受体刺激的途径上起作用。虽然已知特定的激活因子（如T细胞受体刺激或肿瘤坏死因子）使用单个途径，但没有一个途径被完全阐明。为此，我们将使用一种新的筛选方法来发现并最终表征导致HIV基因组转录的新蛋白质。

DESCRIPTION (provided by applicant): The work proposed here has the long-term objective of contributing to the treatment of people with AIDS. We believe that if we develop a deep enough understanding of the molecular biology of HIV growth, we will uncover new targets for anti-retroviral therapy. The specific aims of the program are: 1) to understand the interaction of the NF-kappaB transcription factor with its binding site in the HIV genome and in cellular genes; 2) to understand whether RelB plays a negative role in the transcription of the HIV genome; 3) to identify and clone the genes for the proteins that are involved in making T cells a fertile soil for the growth of HIV. The proposal derives from the understanding that NF-kappaB is a critical transcription factor for expression of the HIV genome. For Aim 1, we will use novel technologies we have recently developed to determine exactly which components of the NF-kappaB family of proteins are responsible for the activity of the factor. We will also extend this work to the study of the cellular genes activated when T cells move from a quiescent state to an active state, a transition from resistance to HIV to permissiveness for viral growth. We wish to understand not only what proteins are involved but also why different genes use subtly different binding sites, and why different stimuli for NF-kappaB activation might lead to different protein requirements on a single DNA site. Aim 2 derives from our recent demonstration that one of the Rel- related subunits that compose NF-kappaB, RelB, plays a negative role in regulation. It can establish thresholds for activation as well as down-regulating transcription of genes that have responded to NF-kappaB. For Aim 3 we will attempt to find new proteins that function on the pathways that lead to activation of HIV permissivity and the concomitant receptor stimulation of latent HIV genomes. Although individual pathways are known to be used by particular activators, like T cell receptor stimulation or tumor necrosis factor, no one pathway is fully elucidated. For this we will use a novel screening methodology to find and ultimately characterize new proteins that lead to transcription of the HIV genome.