Natural Killer (NK) cell regulation of antiviral T cell responses in the pathogenesis of HIV infection

HIV 感染发病机制中自然杀伤 (NK) 细胞对抗病毒 T 细胞反应的调节

• 批准号: MR/M008614/1
• 负责人: Dimitra Peppa
• 金额: $ 93.66万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM008614%2F1
• 关键词: Natural; Killer; NK; cell; regulation

Around 40 million people are currently living with HIV around the globe. HIV remains a leading infectious killer in the world having claimed in excess of 36 million lives to date. Infection with HIV targets the immune system and leads to progressive deterioration of people's ability to survey for and fend off infections and some types of cancer. As the virus impairs and destroys the function of immune cells, affected individuals become gradually more immunocompromised. The most advanced stage of HIV infection is AIDS. Although there is no cure for HIV to date, combination therapy with anti-HIV agents called antiretroviral therapy (ART), prevents the virus from multiplying in the body but cannot eradicate it, stalling the destruction of the body's immune cells. Although effective treatment has resulted in obvious health benefits, accumulating toxicity as a result of lifelong therapy and universal access to therapy are remaining concerns. In addition, ongoing activation of the immune system as seen in treated individuals accounts for a significant proportion of non-AIDS health problems and associated deaths. There is therefore a widely acknowledged need for the development of new and innovative treatments to improve current therapies.The main immune cell type fighting the virus, the T cell, is severely impaired and debilitated during chronic infection. In this study we will be investigating the ability of another type of cell called Natural Killer (NK) cell, to kill the beneficial T cells limiting their antiviral potential. Malfunctioning NK cells may also attack healthy T cells, causing chronic disease instead of fighting it.The purpose of this study is to identify the possible NK cell-mediated pathways leading to T cell deletion. We will use blood samples obtained during routine clinical care of patients infected with HIV following informed consent. Blocking these harmful pathways will boost the immune system leading to improved viral control and prevention of chronic disease and complications.

目前，地球仪各地约有4 000万人感染艾滋病毒。艾滋病毒仍然是世界上主要的传染性杀手，迄今已夺去3 600多万人的生命。艾滋病毒感染以免疫系统为目标，导致人们调查和抵御感染和某些类型癌症的能力逐渐恶化。随着病毒损害和破坏免疫细胞的功能，受影响的个体逐渐变得更加免疫功能低下。艾滋病毒感染的最后阶段是艾滋病。虽然迄今为止还没有治愈艾滋病毒的方法，但与抗艾滋病毒药物（称为抗逆转录病毒疗法（ART））的联合疗法可以防止病毒在体内繁殖，但不能根除它，阻止人体免疫细胞的破坏。虽然有效的治疗带来了明显的健康益处，但由于终身治疗和普遍获得治疗而产生的累积毒性仍然令人关切。此外，在接受治疗的个人中看到的免疫系统的持续激活占非艾滋病健康问题和相关死亡的很大比例。因此，人们普遍认为需要开发新的和创新的治疗方法来改善现有的治疗方法。对抗病毒的主要免疫细胞类型T细胞在慢性感染期间严重受损和衰弱。在这项研究中，我们将研究另一种称为自然杀伤（NK）细胞的细胞的能力，以杀死限制其抗病毒潜力的有益T细胞。功能失调的NK细胞也可能攻击健康的T细胞，导致慢性疾病，而不是对抗它。本研究的目的是确定可能导致T细胞缺失的NK细胞介导的途径。我们将使用经知情同意后在HIV感染患者的常规临床护理期间获得的血液样本。阻断这些有害的途径将增强免疫系统，从而改善病毒控制和预防慢性疾病和并发症。

项目成果

CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver.

• DOI: 10.1038/srep26157
• 发表时间: 2016-05-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Stegmann KA;Robertson F;Hansi N;Gill U;Pallant C;Christophides T;Pallett LJ;Peppa D;Dunn C;Fusai G;Male V;Davidson BR;Kennedy P;Maini MK
• 通讯作者: Maini MK

RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses.

• DOI: 10.1016/j.cell.2018.08.064
• 发表时间: 2018-10-04
• 期刊: Cell
• 影响因子: 64.5
• 作者: Bradley T;Peppa D;Pedroza-Pacheco I;Li D;Cain DW;Henao R;Venkat V;Hora B;Chen Y;Vandergrift NA;Overman RG;Edwards RW;Woods CW;Tomaras GD;Ferrari G;Ginsburg GS;Connors M;Cohen MS;Moody MA;Borrow P;Haynes BF
• 通讯作者: Haynes BF

Natural Killer Cells in Human Immunodeficiency Virus-1 Infection: Spotlight on the Impact of Human Cytomegalovirus.

• DOI: 10.3389/fimmu.2017.01322
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Peppa D

Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection.

• DOI: 10.3389/fimmu.2018.00474
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Peppa D;Pedroza-Pacheco I;Pellegrino P;Williams I;Maini MK;Borrow P
• 通讯作者: Borrow P

Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo.

• DOI: 10.1371/journal.ppat.1005788
• 发表时间: 2016-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Gill US;Peppa D;Micco L;Singh HD;Carey I;Foster GR;Maini MK;Kennedy PT
• 通讯作者: Kennedy PT