Modulation of surface markers by HIV-1 Vpu/Vpr and sensitivity to NK cell lysis

HIV-1 Vpu/Vpr 对表面标志物的调节以及对 NK 细胞裂解的敏感性

• 批准号: 7760295
• 负责人: Edward Barker
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760295
• 关键词: Accidents; Affect; Antigens; Binding Proteins; CD4 Positive T Lymphocytes; Cell Degranulation; Cell surface; Cells; Cessation of life; Cytolysis; Deterioration; Down-Regulation; Effectiveness; Family; Functional disorder; Genes; Goals; HIV; HIV Infections; HIV-1; HIV-2; Immune; Immune response; Immune system; Knowledge; Laboratory Finding; Learning; Life Cycle Stages; Ligands; Lytic; Mediating; Methods; Modeling; Molecular; NK Cell Activation; NTB-A; Natural Killer Cells; Phosphotransferases; Proteins; Receptor Activation; Reporting; Resistance; Role; Signal Transduction; Surface; System; Testing; Ubiquitination; Up-Regulation; Upper arm; Viral; Viral Proteins; Virion; Virus; cytotoxic; killings; member; novel; novel therapeutic intervention; prevent; protein expression; public health relevance; receptor; tissue culture; ubiquitin ligase; vpu Protein

DESCRIPTION (provided by applicant): HIV induces a progressive and often irreversible deterioration of the immune system. Through years of experimentation and observation, we have learned that immune responses to HIV do exist and have a range of effectiveness. However, we have also learned about an insidious aspect of the HIV life cycle that enables the virus to persist in the host and to cause immune deterioration. We are referring to the virus' ability to avoid and suppress the immune response. Natural killer (NK) cells are an understudied arm of the immune response against HIV, but are recognized as being crucial in the defense against other viruses. Natural killer cells have the ability to recognize virally infected cells and induce their death via a lytic mechanism, preventing formation of progeny virus particles. Part of the reason that NK cells are not sufficiently studied, in our view, is that HIV infected cells in tissue culture are insensitive to NK killing. In the recent years we have become increasingly aware that the resistance of HIV infected cells to NK is not an accident, but is the result of the combined action of viral proteins that act to suppress the function of NK cells. The viral protein Nef, for example, was the first HIV protein to be found to carry out such a role. The key findings from the laboratories of Drs. Barker and Planelles, which propelled the present studies, show that two other HIV proteins, Vpu and Vpr, manipulate the host cell to also induce resistance to NK lysis. Vpu and Vpr perform this task in a manner that is very distinct from and complementary to that by which Nef acts. The immediate goal of the proposed studies is to understand the mechanisms by which Vpu and Vpr manipulate the sensitivity to NK lysis. The ultimate goal of these studies will be to use this knowledge to devise novel therapeutic approaches aimed at rendering HIV infected cells sensitive to NK killing. PUBLIC HEALTH RELEVANCE: HIV infected cells are resistant to the action of natural killer cells, an important arm of the immune response against many other viruses. Our studies reveal previously unknown activities of viral proteins from HIV-1 that render infected cells resistant to NK recognition and therefore allow HIV to escape this arm of the immune response. We propose to understand the mechanisms by which Vpu and Vpr manipulate the sensitivity to NK lysis. The ultimate goal of these studies will be to use this knowledge to devise novel therapeutic approaches aimed at rendering HIV infected cells sensitive to NK killing.

描述（由申请人提供）：HIV诱导免疫系统的进行性且通常不可逆的恶化。通过多年的实验和观察，我们已经了解到，对艾滋病毒的免疫反应确实存在，并具有一系列有效性。然而，我们也了解到艾滋病毒生命周期的一个阴险方面，它使病毒能够在宿主体内持续存在，并导致免疫力下降。我们指的是病毒避免和抑制免疫反应的能力。自然杀伤（NK）细胞是针对HIV的免疫反应的一个未充分研究的分支，但被认为是防御其他病毒的关键。自然杀伤细胞具有识别病毒感染细胞并通过裂解机制诱导其死亡的能力，从而防止子代病毒颗粒的形成。在我们看来，NK细胞没有得到充分研究的部分原因是组织培养中的HIV感染细胞对NK细胞杀伤不敏感。近年来，我们越来越意识到，HIV感染细胞对NK细胞的抗性不是偶然的，而是抑制NK细胞功能的病毒蛋白的联合作用的结果。例如，病毒蛋白Nef是第一个被发现具有这种作用的HIV蛋白。Barker和Planelles博士实验室的关键发现推动了本研究，表明另外两种HIV蛋白Vpu和Vpr操纵宿主细胞也诱导对NK裂解的抗性。Vpu和Vpr以一种与Nef的行为非常不同和互补的方式执行这项任务。所提出的研究的直接目标是了解Vpu和Vpr操纵对NK细胞溶解的敏感性的机制。这些研究的最终目标将是利用这些知识来设计新的治疗方法，旨在使HIV感染细胞对NK杀伤敏感。公共卫生相关性：HIV感染的细胞对自然杀伤细胞的作用有抵抗力，自然杀伤细胞是对抗许多其他病毒的免疫反应的重要武器。我们的研究揭示了以前未知的HIV-1病毒蛋白的活性，使感染的细胞对NK识别产生抗性，从而使HIV逃避免疫反应的这一臂。我们建议了解Vpu和Vpr操纵NK细胞溶解敏感性的机制。这些研究的最终目标将是利用这些知识来设计新的治疗方法，旨在使HIV感染细胞对NK杀伤敏感。