The Intersection of Sex, Innate Immunity and the HIV Reservoir

摘要 长期存活的静息记忆CD 4 + T细胞的持续HIV感染，对当前抗逆转录病毒治疗无反应 抗逆转录病毒疗法（ART）和不受免疫监视的影响仍然是实现 艾滋病的解药病毒的潜伏状态在感染后几天内建立，并随着时间的推移非常缓慢地衰减。 半衰期为40-44个月，需要终身抗病毒治疗以抑制感染复发。给定 全世界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， 与免疫疗法联合使用，破坏持续的艾滋病毒感染，以清除含有重新激活的病毒的细胞 仍然是寻求治愈艾滋病毒感染的高度优先事项。免疫增强是不可或缺的组成部分 有效清除持续感染的细胞。这样的工作不仅需要广泛的知识， 更有力地诱导潜伏感染细胞表达HIV抗原的有效方法， 可能阻碍清除潜伏期出现的含病毒细胞的因素。定义效果 潜伏期逆转剂（LRA）对免疫系统的各种功能是至关重要的，如果这种组合 治疗是要部署的。虽然有几项研究侧重于提高适应性的方法， 在潜伏期逆转的背景下，对先天性免疫应答的研究很少。 免疫力I型干扰素影响先天性和适应性免疫应答。它们诱导细胞 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，人们对生物学的影响知之甚少。 性别对增强免疫力的能力，有效地清除含有重新激活的潜伏艾滋病毒的细胞。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，而且还可能影响清除艾滋病毒的能力。 重新激活细胞。我们的初步数据表明，I型干扰素和雌激素信号都受到LRA的调节。 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，如 scRNAseq和ERα特异性蛋白水解靶向嵌合体（PROTAC），以1）定义新出现的蛋白水解靶向嵌合体的作用 和基准LRA对I型干扰素信号传导的作用; 2）质疑I型干扰素信号传导的作用， 3）检查I型干扰素和雌激素信号传导的相互作用， 调节免疫反应并确定LRA对该过程的影响。从这件事中获得的知识 该项目将推动该领域的发展，为艾滋病毒治愈的所有人口的成功疗法， 人 .

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. .