HIV Induced Cellular Pathology

描述(申请人提供)：这里提出的工作的长期目标是促进艾滋病患者的治疗。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靶点。该计划的具体目标是：1)了解核因子-kappaB转录因子与其在HIV基因组和细胞基因中的结合部位的相互作用；2)了解RelB是否在HIV基因组的转录中起负面作用；3)鉴定和克隆使T细胞成为HIV生长的肥沃土壤所涉及的蛋白质的基因。这一建议源于对核因子-kappaB是艾滋病毒基因组表达的关键转录因子的理解。对于目标1，我们将使用我们最近开发的新技术来准确确定核因子-kappaB家族的哪些蛋白质组分负责该因子的活性。我们还将把这项工作扩展到T细胞从静止状态到活动状态时激活的细胞基因的研究，T细胞从对艾滋病毒的抵抗转变为对病毒生长的许可。我们不仅希望了解参与其中的蛋白质，而且还希望了解为什么不同的基因使用细微不同的结合部位，以及为什么不同的核因子-kappaB激活刺激可能导致同一DNA位点上不同的蛋白质需求。目标2源于我们最近的研究，即组成核因子-kappaB的REL相关亚基之一，RelB，在调节中起着负面作用。它可以为对核因子-kappaB有反应的基因的激活和下调转录设定阈值。对于目标3，我们将尝试寻找在导致激活HIV通透性和伴随潜伏的HIV基因组的受体刺激的途径上起作用的新的蛋白质。虽然已知单个通路被特定的激活物使用，如T细胞受体刺激或肿瘤坏死因子，但没有一个通路被完全阐明。为此，我们将使用一种新的筛选方法来寻找并最终确定导致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.