Targeting natural killer cells to HIV in intravenous drug users

项目总结/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。一种有效的疫苗可以 预防每年持续发生的约200万新感染，并针对潜伏性- 感染的细胞可以大大推进治疗策略。然而，传统的基于 引发适应性B和T细胞应答通常导致无效的狭窄免疫应答 对抗全球范围内传播的各种各样的艾滋病病毒株。对个人来说，挑战更为严峻 由于目前的疫苗接种工作完全集中在性传播疾病上， HIV病毒株，其通常仅与单一菌株建立感染，并且必须通过上皮细胞， 建立感染的屏障。相比之下，通过注射吸毒感染艾滋病毒的人， 更有可能感染具有不同抗原特性的多种菌株。我们建议开创一个 一种通过利用自然杀伤（NK）细胞来提高HIV免疫靶向的新方法， 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细胞在其抗病毒作用中具有惊人的特异性。 应答NK细胞和感染者之间的通讯可以控制免疫的质量和数量。 免疫反应，影响杀死感染细胞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毒品传播的艾滋病毒株中的差异。使用先进的单- 细胞技术，我们还将定义精确的NK细胞亚群和激活途径， 一个有效的NK细胞反应，以及如何控制这些途径是维持在表观遗传水平。 总之，这些方法将确定特定先天靶向所需的病毒和细胞成分 这使我们能够在开发疫苗和疗法时做出明智的选择， 促进病毒根除的反应。

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.