Targeting natural killer cells to HIV in intravenous drug users

项目摘要/摘要 利用我们的免疫系统来对抗艾滋病毒提供了诱人的可能性。一种有效的疫苗可能 防止每年持续发生的约200万新感染，并潜伏着免疫靶向- 被感染的细胞可以显著推进治愈策略。然而，传统的方法基于 激发适应性B和T细胞反应通常会导致无效的狭窄免疫反应 以对抗在世界各地传播的艾滋病毒毒株的巨大多样性。对于个人来说，挑战更加严峻 通过注射吸毒感染，因为目前的疫苗工作仅专注于性传播 HIV毒株，通常只有一种毒株感染，必须通过上皮组织 建立感染的屏障。相比之下，通过注射吸毒感染艾滋病毒的个人是 更有可能感染具有不同抗原性的多个菌株。我们建议开创一种 通过利用自然杀伤(NK)细胞提高HIV免疫靶向性的新方法，具有特定的 强调通过注射吸毒传播的独特菌株。 我们有令人兴奋的新数据表明，NK细胞在抗病毒方面具有惊人的特异性 回应。NK细胞与感染者之间的通讯可以控制NK细胞的质量和数量 免疫反应，影响对感染细胞的杀伤和分泌细胞因子之间的平衡 增强或抑制免疫反应。为了确定控制NK质量的机制 细胞对HIV的反应，我们建议确定驱动NK细胞激活和逃逸的病毒成分， 以及这些成分在通过注射吸毒传播的艾滋病毒毒株中有何不同。使用先进的单人- 细胞技术，我们还将定义准确的NK细胞亚群和激活途径所需的生成 有效的NK细胞反应以及如何在表观遗传水平上控制这些途径。 这些方法将共同识别特定先天靶向所需的病毒和细胞成分 使我们能够在疫苗和治疗方法的开发中做出明智的选择，以诱导NK细胞 促进根除病毒的反应。

Project Summary/Abstract Harnessing our immune system to fight HIV presents tantalizing possibilities. An effective vaccine could prevent the ~2 million new infections that continue to occur each year, and immune targeting of latently- infected cells could significantly advance cure strategies. However, the traditional approaches based on eliciting adaptive B and T cell responses have typically led to narrow immune responses that are not effective against the vast diversity of HIV strains circulating worldwide. The challenge is more acute for individuals infected through injection drug use, as current vaccine efforts are exclusively focused on sexually-transmitted HIV strains, which typically establish infection with only a single strain and must pass through an epithelial barrier to establish infection. In contrast, individuals who are infected with HIV through injection drug use are more likely to be infected with multiple strains with different antigenic properties. We propose pioneering a novel approach to improve immune targeting of HIV by harnessing natural killer (NK) cells, with a particular emphasis on the unique strains transmitted through injection drug use. We have exciting new data indicating that NK cells have a surprising degree of specificity in their antiviral responses. The communication between the NK cell and an infected can control the quality and the quantity of the immune response, affecting the balance between killing of infected cells and secreting cytokines that can enhance or dampen the immune response. In order to define the mechanisms that control the quality of the NK cell responses to HIV, we propose identifying the viral components that drive NK cell activation and escape, and how these components differ in HIV strains transmitted through injection drug use. Using advanced single- cell techniques, we will also define the precise NK cell subsets and activation pathways required to generate an effective NK cell response and how control of these pathways is maintained at the epigenetic level. Together, these approaches will identify the viral and cellular components required for specific innate targeting of HIV, allowing us to make informed choices in the development of vaccines and therapeutics to elicit NK cell responses that promote viral eradication.