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

鉴定药物靶向的 IFN 刺激基因在 ART 治疗的 HIV-1 感染期间介导免疫激活

• 批准号: 10405575
• 负责人: ROMEL D MACKELPRANG
• 金额: $ 72.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-06 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405575
• 关键词: Acquired Immunodeficiency Syndrome; Acute; African Green Monkey; Aftercare; Age; Aging; Bioinformatics; Biological Process; Biopsy; Blood; CCL4 gene; CD4 Positive T Lymphocytes; Cell Count; Cells; Cercocebus; Cessation of life; Chronic; Chronic Disease; Climacteric; Clinical; Clinical Data; Combined Modality Therapy; Couples; Cryopreservation; Data; Development; Disease; Dissection; Drug Targeting; Drug or chemical Tissue Distribution; Drug usage; Duodenum; Gene Expression; General Population; Genes; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immune system; Immunologic Markers; Immunologics; In Vitro; Individual; Infection; Inflammatory; Interferons; Kinetics; Knowledge; Lead; Life Expectancy; Longevity; Macaca mulatta; Measures; Mediating; Modeling; Morbidity - disease rate; Opportunistic Infections; Participant; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Population; Process; Quality of life; RNA; Recovery; Regulation; Research; Risk; Role; SIV; Time; Translating; Translations; Virus; Virus Diseases; Virus Replication; antiretroviral therapy; chronic infection; cohort; comorbidity; design; drug repurposing; exhaust; exhaustion; experience; genetic signature; immune activation; improved; in vitro Model; in vivo; men; mortality; mortality risk; nonhuman primate; novel; novel strategies; novel therapeutics; rectal; response; sample archive; targeted treatment; transcriptome sequencing

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.

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 疾病从快速发展到艾滋病和死亡到一种可控制的慢性病。然而，艺术- 接受治疗的人的发病率和死亡率仍然高于普通人群。作为更多 人们接受抗逆转录病毒治疗，接受艾滋病毒-1治疗的人口年龄我们需要新的战略来使他们的 寿命和生活质量。因此，需要进行研究来阐明其背后的生物学过程。 增加发病率和死亡率的风险，并将这一知识转化为新的治疗方法。 这项建议试图评估在感染HIV-1期间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。在所有病毒之后 在感染方面，急性免疫反应对于降低病毒水平至关重要。随后，这些回应是 关了。然而，在HIV-1感染中，即使在病毒水平降低后，免疫活性仍会增强 通过ART达到非常低的水平-这些免疫反应永远不会关闭。随着时间的推移，持续的激活 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。 HIV-1慢性免疫激活的一个因素是干扰素刺激基因的表达 (ISGS)持续上调。人类携带着数百个具有多种功能的ISG，包括直接 抗病毒活性以及对其他ISGs和免疫反应的调节。我们的小组已经记录了ISG 在感染HIV-1期间，病毒水平持续上升。我们假设以特定的ISG为目标可能是 减少HIV-1感染期间慢性免疫激活的策略，同时允许 免疫反应保持有效。 这项提案的目的是确定在HIV-1期间对慢性免疫激活有贡献的ISGs 感染，并将这些数据转换为现有药物的排序列表，这些药物可以作为辅助药物重新使用 用ART进行治疗。为此，我们将在感染HIV-1的个体中检测ISG的表达 在ART开始后，并将他们的ISG表达水平与未感染的参与者进行比较。在艾滋病病毒感染者中- 1感染的参与者，我们还将确定ISG的表达与HIV-1临床参数和 免疫学标志物。为了更清楚地定义艺术在ISG表达中的作用，我们还将进行 我们用ART直接处理HIV-1感染者的细胞并比较ISG的体外研究 治疗前后的表达情况。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影响，使用对ISG水平和免疫激活的影响。 最后，我们将把研究ART和ISG表达的数据与有关基因表达的数据结合起来 在其他感染期间，以及可用于治疗这些其他感染的药物。通过这样做，我们的目标是确定 可以改变用途的药物，用于治疗HIV-1感染期间的慢性免疫激活。

项目成果

Upregulation of PTPRC and Interferon Response Pathways in HIV-1 Seroconverters Prior to Infection.

• DOI: 10.1093/infdis/jiac498
• 发表时间: 2023-03-01
• 期刊: The Journal of infectious diseases
• 作者: Li Y;Lefebvre F;Nakku-Joloba E;Ronald A;Gray G;de Bruyn G;Kiarie J;Celum C;Cameron MJ;Lingappa JR;Mackelprang RD
• 通讯作者: Mackelprang RD