NK cell memory subsets and their impact on HIV disease progression and vaccination

NK 细胞记忆亚群及其对 HIV 疾病进展和疫苗接种的影响

基本信息

批准号：
10673142
负责人：
Kawthar Machmach leggat
金额：
$ 26.34万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673142
关键词：
ARID Domain Acute Adenovirus Vector Adenoviruses Adjuvant Antibodies Antigens Attention Autologous BTB/POZ Domain Biological Assay COVID-19 therapeutics Cell physiology Cells Characteristics Chronic Development Disease Disease Progression Epigenetic Process FDA approved Flow Cytometry Future Goals HIV HIV Infections Health Human IgG Receptors Immune Immune response Immune system Immunotherapeutic agent Infection Interferons Intervention Knowledge Maps Mediating Memory Military Personnel Molecular NK Cell Activation Natural Killer Cells Pharmacologic Substance Phase Phenotype Play Prevention Research Research Proposals Role SIV Specificity Specimen Testing Vaccination Vaccines Viral Viral Load result Virus Diseases Zinc Fingers adaptive immunity anti-tumor immune response antibody-dependent cell cytotoxicity cohort cytokine cytotoxicity exhaustion immunoregulation improved methylome mosaic nonhuman primate novel pandemic disease pathogenic virus programs response therapeutically effective transcription factor vaccination strategy vaccine platform vaccine strategy vaccine trial vector vector vaccine vector-based vaccine viral pandemic

项目摘要

PROJECT SUMMARY/ABSTRACT: Despite the many options for HIV treatment and prevention, an efficacious and safe vaccine remains a key component in efforts to end the pandemic. Natural killer (NK) cells play a crucial role in anti-viral immune responses. Not only have they have been shown to play a critical role in host protection through direct targeting of virally infected cells and also via NK-mediated antibody dependent cellular cytotoxicity. However, recent studies suggest a more encompassing role for NK cells since they can develop into long-lived memory cells and acquire antigen specificity. Thus, there is a need to elucidate the cellular and molecular mechanisms regulating NK cell responses to natural HIV infection and HIV vaccination. The long-term goal of our research is to devise safe and effective vaccine strategies to counter this viral pandemic. To achieve this, we have focused on understanding the mechanisms that mobilize NK cells, with particular attention to inducing NK cell cytotoxicity. The objective of this proposal is to identify qualitative and quantitative features of NK cell activation and differentiation inducted by HIV natural infection and Adenovirus (Ad)-vectored-based vaccination. The overarching hypothesis is that both natural HIV infection and Ad-vectored HIV vaccination will induce the activation and maturation of NK cells and subsequent development of memory NK cells. Our rationale is that understanding the mechanisms regulating NK cell activation and functionality, in addition to the cellular and molecular mechanisms of antibody-mediated NK cell functions, in response to both natural HIV infection and vaccination, will be beneficial for establishing translational interventions against HIV and other viral infections. Our specific aims will test the following: Aim 1: Differentiate memory NK cell subsets and their potential impact on HIV disease progression and response to Ad26.Mos.HIV vaccination; and Aim 2: Map and compare memory NK cell epigenetic signatures in response to HIV natural infection and Ad26.Mos.HIV vaccination. Upon conclusion, our analysis will help to fill the current knowledge gap regarding NK cell memory development in responses to both natural HIV infection and HIV vaccination. This knowledge is important because we expect it to identify novel aspects of the immune system we can modulate to our advantage against viral pathogens, and ultimately use NK cells as part of future effective therapeutic vaccine strategies.

项目概要/摘要：尽管艾滋病毒治疗和预防有多种选择，但有效且安全的疫苗仍然是关键结束这一流行病的努力的一部分。自然杀伤（NK）细胞在抗病毒免疫中发挥着至关重要的作用回应。它们不仅被证明通过直接靶向在宿主保护中发挥关键作用病毒感染细胞的作用以及 NK 介导的抗体依赖性细胞毒性。然而，最近研究表明 NK 细胞具有更广泛的作用，因为它们可以发育成长寿的记忆细胞获得抗原特异性。因此，有必要阐明调节的细胞和分子机制。 NK 细胞对自然 HIV 感染和 HIV 疫苗接种的反应。我们研究的长期目标是设计应对这种病毒大流行的安全有效的疫苗策略。为了实现这一目标，我们重点关注了解动员 NK 细胞的机制，特别关注诱导 NK 细胞的细胞毒性。该提案的目的是确定 NK 细胞激活的定性和定量特征以及 HIV自然感染和腺病毒（Ad）载体疫苗接种诱导分化。这总体假设是自然 HIV 感染和 Ad 载体 HIV 疫苗接种都会诱发 NK 细胞的激活和成熟以及记忆 NK 细胞的后续发育。我们的理由是了解调节 NK 细胞激活和功能的机制，以及细胞和抗体介导的 NK 细胞功能的分子机制，响应自然 HIV 感染和疫苗接种将有利于建立针对艾滋病毒和其他病毒感染的转化干预措施。我们的具体目标将测试以下内容：目标 1：区分记忆 NK 细胞亚群及其潜在影响 HIV 疾病进展和 Ad26.Mos.HIV 疫苗接种反应；目标 2：映射和比较内存 NK 细胞表观遗传特征响应 HIV 自然感染和 Ad26.Mos.HIV 疫苗接种。之上总之，我们的分析将有助于填补当前有关 NK 细胞记忆发育的知识空白对自然艾滋病毒感染和艾滋病毒疫苗接种的反应。这些知识很重要，因为我们期望它为了识别免疫系统的新方面，我们可以对其进行调节以对抗病毒病原体，并且最终使用 NK 细胞作为未来有效治疗性疫苗策略的一部分。