The Intersection of Sex, Innate Immunity and the HIV Reservoir

性别、先天免疫和艾滋病病毒库的交叉点

• 批准号: 10616206
• 负责人: Nancie M Archin
• 金额: $ 59.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616206
• 关键词: Adaptive Immune System; Affect; Antiviral Response; Antiviral Therapy; Benchmarking; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line; Cells; Characteristics; Chronic; Clear Cell; Coculture Techniques; Combined Modality Therapy; Data; Defect; Dendritic Cells; Disease; Disease remission; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Female; Generations; Genes; Genetic; HIV; HIV Antigens; HIV Budding; HIV Infections; HIV-1; Half-Life; Hormonal; Hormonal Change; ISG15 gene; Immune; Immune response; Immunity; Immunoblot Analysis; Immunologic Surveillance; Immunotherapy; Individual; Infection; Innate Immune Response; Integration Host Factors; Interferon Type I; Interferon-alpha; Interferons; Intrinsic factor; Knowledge; Life; Lymphocyte; Lymphoid Cell; Mediating; Mediator of activation protein; Methodology; Methods; Modality; Modeling; Molecular Biology; Myeloid Cells; Natural Immunity; Natural Killer Cells; Outcome; Participant; Periodicity; Persons; Pharmaceutical Preparations; Population; Process; Production; Protac; Proteins; Race; Recrudescences; Rest; Role; Serum; Sex Differences; Signal Transduction; T-Cell Activation; TLR7 gene; Therapeutic; Transcript; Viral; Viral Antigens; Viral Load result; Virion; Virus; Woman; Work; adaptive immune response; adaptive immunity; antiretroviral therapy; arm; base; biological sex; cell age; chronic infection; cytokine; gender difference; immune activation; immune function; immune system function; improved; male; memory CD4 T lymphocyte; men; negative affect; pathogen; promoter; recruit; response; sex; single-cell RNA sequencing; tool

Abstract Persistent HIV infection of long lived resting memory CD4+ T-cells, unresponsive to current antiretroviral therapy (ART) and unaffected by immune surveillance remains a formidable barrier towards efforts to achieve an HIV cure . The latent state of the virus is established within days of infection, and decays very slowly with a half-life of 40-44 months, necessitating life-long antiviral therapy to suppress recrudescence of infection. Given the continuous expansion of the number of HIV-infected individuals on lifelong ART worldwide, modalities to disrupt persistent HIV infection in combination with immunotherapies to clear cells containing reactivated virus remains a high priority in the quest to cure HIV infection. Immune augmentation is an indispensable component of effective clearance of persistently infected cells. Such an undertaking requires broad knowledge of not only effective methods to more robustly induce HIV antigen expression from latently infected cells, but also of factors that may hinder the clearance of cells containing virus emerging from latency. Defining the effect latency reversal agents (LRAs) on the various functions of the immune system is critical if such combination therapies are to be deployed. While several studies have focused on methodologies to improve the adaptive arm of the immune response in the context of latency reversal, there have been minimal studies on innate immunity. Type I interferons influences both the innate and adaptive immune response. They induce cell intrinsic factors to limit the spread of pathogens, including viruses, they modulate the innate immune responses and promote activation of the adaptive immune system. Likewise, little is known about the effect of biological sex on the ability of augmented immunity to effectively clear cells containing reactivated latent HIV. Sex-based differences in innate immunity may influence not only the outcome of HIV infection, but also the ability to clear reactivated cells. Our preliminary data indicate both type I IFN and estrogen signaling are modulated by LRAs. In this project we will employ a comprehensive approach, including the use of state of the art tools such as scRNAseq and ERα specific PROteolysis TArgeting Chimeras (PROTACs) to 1) define the effect of emerging and benchmark LRAs on type I interferon signaling; 2) query the role of type I interferon signaling, on the fate of virus emerging from latency and 3) examine the interplay of type I interferon and estrogen signaling to modulate the immune response and define the effects of LRAs on the process. Knowledge gained from this project will advance the field towards developing successful therapeutics for HIV cure in all populations of people. .

抽象的 长期生活记忆CD4+ T细胞的持续性HIV感染，对电流抗逆转录病毒无反应 治疗（ART）和不受免疫监视的影响仍然是努力实现的巨大障碍 艾滋病毒治愈。病毒的潜在状态在感染的几天内建立 半衰期为40-44个月，必要的终身抗病毒疗法以抑制感染的复发。给出 全世界终身艺术中感染了艾滋病毒感染者人数的持续扩展， 破坏持续的HIV感染与免疫疗法结合到清除含有重新激活病毒的细胞 在寻求治愈艾滋病毒感染的过程中，仍然是一个很高的优先事项。免疫增强是必不可少的组成部分 有效清除持续感染的细胞。这样做的不仅需要广泛的知识 有效的方法可以更牢固地诱导潜在感染细胞的HIV抗原表达，但也是 可能阻碍含有潜伏期病毒的细胞清除的因素。定义效果 如果这种组合 疗法将被部署。虽然几项研究的重点是改善自适应的方法 在潜伏期逆转的背景下，免疫响应的臂，关于先天的研究很少 免疫。 I型干扰物会影响先天和适应性免疫响应。它们会影响细胞 限制病原体传播（包括病毒）的内在因素，它们调节先天免疫反应 并促进自适应免疫系统的激活。同样，对生物学的影响知之甚少 性别对增强免疫学有效清除含有重新激活HIV的细胞的能力。基于性别 先天免疫的差异不仅可能影响艾滋病毒感染的结果，还会影响清除的能力 重新激活的细胞。我们指示I型IFN和雌激素信号传导的初步数据均由LRA调节。 在这个项目中，我们将采用一种全面的方法，包括使用先进的工具，例如 Scrnaseq和ERα特异性蛋白水解靶向嵌合体（Protac）至1）定义出现的效果 和I型干扰素信号传导上的基准LRA； 2）查询I型干扰素信号的作用，在命运上 从潜伏期中出现的病毒和3）检查I型干扰素和雌激素信号的相互作用 调节免疫反应并定义LRA对过程的影响。从中获得的知识 项目将使该领域朝着在所有人群中开发成功治疗艾滋病毒治疗的领域 人们。 。