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

基本信息

批准号：
7897741
负责人：
Edward Barker
金额：
$ 18.78万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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

项目摘要

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 会导致免疫系统进行性且通常不可逆转的恶化。通过多年的实验和观察，我们了解到针对艾滋病毒的免疫反应确实存在，并且具有一系列的有效性。然而，我们也了解到艾滋病毒生命周期的一个阴险的方面，它使病毒能够在宿主体内持续存在并导致免疫功能恶化。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 的免疫反应中未被充分研究的一种细胞，但被认为在防御其他病毒方面至关重要。自然杀伤细胞能够识别病毒感染的细胞并通过裂解机制诱导其死亡，从而防止子代病毒颗粒的形成。我们认为，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 杀伤不敏感。近年来，我们越来越意识到，HIV感染细胞对NK细胞的抵抗并非偶然，而是病毒蛋白联合作用抑制NK细胞功能的结果。例如，病毒蛋白 Nef 是第一个被发现具有这种作用的 HIV 蛋白。博士实验室的主要发现。推动本研究的 Barker 和 Planelles 表明，另外两种 HIV 蛋白 Vpu 和 Vpr 也可以操纵宿主细胞诱导对 NK 裂解的抵抗。 Vpu 和 Vpr 执行此任务的方式与 Nef 的工作方式非常不同且互补。拟议研究的直接目标是了解 Vpu 和 Vpr 操纵 NK 裂解敏感性的机制。这些研究的最终目标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 感染细胞对自然杀伤细胞的作用具有抵抗力，而自然杀伤细胞是针对许多其他病毒的免疫反应的重要组成部分。我们的研究揭示了 HIV-1 病毒蛋白的先前未知的活性，这些活性使受感染的细胞对 NK 识别具有抵抗力，从而使 HIV 能够逃脱免疫反应的这一臂。我们建议了解 Vpu 和 Vpr 操纵 NK 裂解敏感性的机制。这些研究的最终目标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。