Identification of drug-targetable IFN-stimulated genes mediating immune activation during ART-treated HIV-1 infection

摘要 抗逆转录病毒疗法（ART）从根本上改变了HIV-1感染者的生活， 从迅速发展到艾滋病，从死亡到可控制的慢性病。然而，ART- 接受治疗的人的发病率和死亡率仍然高于一般人群。随着更多 我们需要新的策略来使他们的年龄正常化， 寿命和生活质量。因此，需要进行研究以阐明 提高发病率和死亡率的风险，并将这些知识转化为新的治疗方法。 该提案旨在评估HIV-1感染期间的免疫激活如何有助于增加 死亡率和发病率，以及如何将这些知识转化为新的治疗方法。在所有病毒 感染后，急性免疫反应对于降低病毒水平至关重要。随后，这些答复是 关闭.然而，在HIV-1感染中，即使在病毒水平降低后， 降低到非常低的水平-这些免疫反应永远不会关闭。随着时间的推移，持续激活 耗尽免疫系统，为更多的病毒复制、机会性感染和艾滋病扫清道路。 在HIV-1期间慢性免疫激活的一个促成因素是IFN刺激基因的表达， （ISG）持续上调。人类携带数百个ISG，具有许多功能，包括直接 抗病毒活性和调节其他ISG和免疫应答。我们的团队记录了ISG 在HIV-1感染期间，其水平持续升高。我们假设，针对特定的ISG可能是一种 一种减少HIV-1感染期间慢性免疫激活的策略，同时允许HIV-1感染的其他成分 免疫反应保持有效。 本提案的目的是确定在HIV-1感染期间促进慢性免疫激活的ISG。 并将这些数据转化为现有药物的排名列表， 为了做到这一点，我们将在治疗前和治疗后测量HIV-1感染者中ISG的表达。 在开始ART后，将他们的ISG表达水平与未感染的参与者进行比较。在艾滋病毒中- 1感染的参与者，我们还将确定ISG表达如何与临床HIV-1参数相关， 免疫学标记为了更清楚地定义ART对ISG表达的作用，我们还将进行 在体外研究中，我们直接用ART处理来自HIV-1感染个体的细胞， 治疗前后的表达。这些研究将提供有关ART效果的详细信息 通过减少病毒复制和药物本身的直接作用，在ISG水平和免疫激活上使用。 最后，我们将整合ART和ISG表达研究的数据与基因表达相关的数据 以及可以用来治疗这些感染的药物。通过这样做，我们的目标是确定 这些药物可用于治疗HIV-1感染期间的慢性免疫激活。

ABSTRACT Antiretroviral therapy (ART) fundamentally altered the lives of people living with HIV-1 by shifting the disease course from rapid progression to AIDS and death to a manageable chronic disease. However, ART- treated people still experience higher rates of morbidity and mortality than the general population. As more people are treated with ART and the HIV-1 treated population ages we need new strategies to normalize their life span and quality of life. Therefore, research is needed to elucidate the biological processes underying the heightened risk of morbidity and mortality and to translate this knowledge into new treatments. This proposal seeks to evaluate how immune activation during HIV-1 infection contributes to increased mortality and morbidity, and how this knowledge can be translated into novel treatments. Following all viral infections, acute immune responses are critical for reducing virus levels. Subsequently, those responses are turned off. In HIV-1 infection, however, heightend immune activation persists even after virus levels are reduced to very low levels by ART—those immune responses are never turned off. Over time, persistant activation exhausts the immune system, clearing the way for more viral replication, opportunistic infections and AIDS. One contributing factor to chronic immune activation during HIV-1 is that expression of IFN stimulated genes (ISGs) is persistently up-regulated. Humans carry hundreds of ISGs with many functions including direct antiviral activity and regulation of other ISGs and immune responses. Our group has documented that ISG levels are persistently increased during HIV-1 infection. We hypothesize that targeting specific ISGs may be a strategy for reducing chronic immune activation during HIV-1 infection while allowing other compontents of the immune response to remain effective. The objective of this proposal is to identify ISGs contributing to chronic immune activation during HIV-1 infection and to translate those data into a ranked list of existing drugs that could repurposed as adjunctive treatments with ART. To do so, we will measure ISG expression among HIV-1 infected indivuals before and after initiation of ART, and will compare their ISG expression levels to uninfected participants. Among the HIV- 1 infected participants, we will also determine how ISG expression relates to clinical HIV-1 parameters and immunologic markers. In order to more clearly define the role of ART on ISG expression we will also conduct in vitro studies in which we directly treat cells from HIV-1 infected individuals with ART and compare ISG expression before and after treatment. These studies will provide detailed information about the effects of ART use on ISG levels and immune activation by reducing viral replication and direct effects of the drugs themselves. Finally, we will integrate data from our studies of ART and ISG expression with data regarding gene expression during other infections and drugs that can be used to treat those other infections. By doing so, we aim to identify drugs that can be repurposed to treate chronic immune activation during HIV-1 infection.