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

描述(由申请人提供)：艾滋病毒会导致免疫系统的进行性且往往是不可逆转的恶化。通过多年的实验和观察，我们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隐蔽方面，使病毒能够在宿主中持续存在，并导致免疫恶化。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的免疫反应的一个未被研究的手臂，但被认为在防御其他病毒方面起着关键作用。自然杀伤细胞具有识别病毒感染细胞的能力，并通过裂解机制诱导它们死亡，防止后代病毒颗粒的形成。在我们看来，NK细胞没有得到充分研究的部分原因是，组织培养中感染艾滋病毒的细胞对NK杀伤不敏感。近年来，我们越来越意识到，HIV感染细胞对NK细胞的耐药性不是偶然的，而是病毒蛋白共同作用的结果，这些蛋白抑制了NK细胞的功能。例如，病毒蛋白Nef是第一个被发现具有这种作用的艾滋病毒蛋白。推动这项研究的Barker和Planelle博士的实验室的关键发现表明，另外两种HIV蛋白，VPU和VPR，也操纵宿主细胞来诱导对NK裂解的抵抗。VPU和VPR执行这项任务的方式与Nef的方式非常不同，并相互补充。这项研究的近期目标是了解VPU和VPR控制NK细胞裂解敏感性的机制。这些研究的最终目标将是利用这一知识设计新的治疗方法，旨在使艾滋病毒感染细胞对NK杀伤敏感。与公共卫生相关：感染艾滋病毒的细胞对自然杀伤细胞的活动具有抵抗力，自然杀伤细胞是对抗许多其他病毒的免疫反应的重要手臂。我们的研究揭示了HIV-1病毒蛋白以前未知的活性，使感染细胞对NK识别产生抵抗，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控制NK裂解敏感性的机制。这些研究的最终目标将是利用这一知识设计新的治疗方法，旨在使艾滋病毒感染细胞对NK杀伤敏感。

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.