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

• 批准号: 10534505
• 负责人: Kawthar Machmach leggat
• 金额: $ 21.93万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 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/10534505
• 关键词: ARID Domain; Acute; Adenovirus Vector; Adjuvant; Antibodies; Antigens; Antiviral Response; 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; Lead; Maps; Mediating; Memory; Military Personnel; Molecular; Mosaicism; 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; base; cohort; cytokine; cytotoxicity; exhaustion; immunoregulation; improved; methylome; nonhuman primate; novel; pandemic disease; pathogenic virus; programs; response; therapeutically effective; transcription factor; vaccination strategy; vaccine platform; vaccine strategy; vaccine trial; vector vaccine; vector-based vaccine

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.

项目总结/摘要： 尽管艾滋病毒的治疗和预防有许多选择，但有效和安全的疫苗仍然是关键。 这是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起着关键作用 应答它们不仅被证明通过直接瞄准在宿主保护中发挥关键作用， 病毒感染的细胞，也通过NK介导的抗体依赖性细胞毒性。但最近的 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，有必要阐明细胞和分子机制，调节 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 安全和有效的疫苗战略，以应对这一病毒大流行。为了实现这一目标，我们专注于 了解动员NK细胞的机制，特别注意诱导NK细胞的细胞毒性。 本提案的目的是确定NK细胞活化的定性和定量特征， 由HIV自然感染和基于腺病毒（Ad）载体的疫苗接种诱导的分化。的 总体假设是，自然的HIV感染和Ad载体的HIV疫苗接种都将诱导 NK细胞的活化和成熟以及随后记忆NK细胞的发育。我们的理由是， 了解调节NK细胞活化和功能的机制，除了细胞和 抗体介导的NK细胞功能的分子机制，在响应自然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疾病进展和对Ad26.Mos.HIV疫苗接种的反应;以及目标2：映射和比较记忆 NK细胞表观遗传特征对HIV自然感染和Ad26.Mos.HIV疫苗接种的应答后 结论，我们的分析将有助于填补目前关于NK细胞记忆发育的知识空白， 对自然感染艾滋病毒和接种艾滋病毒疫苗的反应。这些知识很重要，因为我们期望它 为了确定免疫系统的新方面，我们可以调节我们对病毒病原体的优势， 最终使用NK细胞作为未来有效治疗疫苗策略的一部分。