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 长寿命静息记忆 CD4+ T 细胞持续感染 HIV，对当前的抗逆转录病毒药物无反应 治疗（ART）且不受免疫监视的影响仍然是实现目标的巨大障碍 HIV 治愈 病毒的潜伏状态在感染后几天内就建立起来，并且随着时间的推移而非常缓​​慢地消退。 半衰期为 40-44 个月，需要终生抗病毒治疗以抑制感染复发。 全球接受终身抗逆转录病毒治疗的艾滋病毒感染者人数不断增加， 持续破坏 HIV 感染并结合免疫疗法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，免疫增强仍然是一个重要的优先事项。 有效清除持续感染的细胞不仅需要广泛的知识。 更强有力地诱导潜伏感染细胞表达 HIV 抗原的有效方法，而且 可能阻碍含有病毒的细胞从潜伏期中清除的因素。 潜伏期逆转剂（LRAs）对免疫系统的各种功能至关重要，如果这种组合 虽然有几项研究重点关注改善适应性的方法。 在潜伏期逆转的背景下，免疫反应的手臂，对先天性的研究很少 I 型干扰素影响先天性和适应性免疫反应。 限制病原体（包括病毒）传播的内在因素，它们调节先天免疫反应 并促进适应性免疫系统的激活同样，人们对生物的作用知之甚少。 性别对增强免疫力有效清除含有重新激活的潜伏艾滋病毒的细胞的能力的影响。 先天免疫的差异可能不仅影响艾滋病毒感染的结果，还影响清除艾滋病毒的能力 我们的初步数据表明 I 型 IFN 和雌激素信号传导均受 LRA 调节。 在这个项目中，我们将采用综合方法，包括使用最先进的工具，例如 scRNAseq 和 ERα 特异性蛋白水解靶向嵌合体 (PROTAC) 1) 定义了新兴的效果 以及 I 型干扰素信号传导的基准 LRA；2) 询问 I 型干扰素信号传导对命运的作用； 病毒从潜伏期出现，3) 检查 I 型干扰素和雌激素信号传导的相互作用 调节免疫反应并定义 LRA 对该过程的影响。 该项目将推动该领域向所有人群开发成功的艾滋病毒治疗方法 人们。 。