Targeting the HIV/SIV reservoir at time of ART initiation

在开始 ART 时针对 HIV/SIV 病毒库

• 批准号: 10443751
• 负责人: Afamefuna Okoye
• 金额: $ 81.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443751
• 关键词: Acute; Address; Agonist; Alleles; Antigens; Bar Codes; Biological Markers; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinic; Clinical Trials; Collaborations; Data; Development; Disease Progression; Disease remission; Dose; Economic Burden; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Frequencies; Gene Expression; Genetic Transcription; Goals; Grant; HIV; HIV Infections; Health; Human; Immune; Immune response; In Vitro; Individual; Infection; Interleukin-15; Interruption; Intervention; Kinetics; Lead; Life; Life Expectancy; Location; Lymphoid Tissue; Macaca; Macaca mulatta; Measurable; Mediating; Modeling; Newly Diagnosed; Persons; Pilot Projects; Production; Prognosis; Protein Kinase C; Relapse; Reporting; Risk; SIV; Safety; Sampling; Shock; Societies; T cell response; Techniques; Testing; Therapeutic Effect; Time; Tissues; Toxic effect; Treatment Efficacy; Variant; Viral; Viral Antigens; Viral Cytopathogenic Effect; Viral reservoir; Virus; Virus Activation; Virus Diseases; Virus Replication; acute infection; antiretroviral therapy; base; cell killing; clinically relevant; cytotoxic CD8 T cells; effector T cell; efficacy testing; improved; in vivo; latent HIV reservoir; migration; nonhuman primate; novel; novel strategies; novel therapeutic intervention; prevent; purge; simian human immunodeficiency virus; social stigma; success; treatment effect; viral rebound

PROJECT SUMMARY Antiretroviral therapy (ART) has dramatically improved the prognosis of people living with human immunodeficiency virus (HIV) infection. However, ART alone cannot eradicate the infection and therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and resumption of disease progression. Unfortunately, in addition to persistent stigma associated with HIV infection, lifelong treatment entails both health risks to treated individuals and a significant economic burden to society. As such, there is a desperate need to develop novel therapeutic interventions that can cure HIV infection. It is now well established that initiation of ART in the first days/weeks after infection does not prevent the establishment of a long-lived viral reservoir, although it is effective at reducing its size. Another strategy aimed at reducing the reservoir is to induce HIV gene expression in individuals on suppressive ART with the goal of eliminating latently infected cells, which could ultimately lead to virus eradication. However, purging the HIV reservoir not only requires the induction of viral replication by latency-reversing agents (LRA) but also the elimination of these reactivating latently-infected cells by either viral cytopathic effects or immune cell-mediated killing, so called “shock and kill”. This killing is often inefficient when LRAs are administered to HIV-infected individuals after several years of ART, possibly due to low level antigen expression, negative impact of LRAs on clearance mechanisms or the low frequencies of effective HIV-specific CD8+ T cells. Here we propose to evaluate a novel strategy in which an LRA is administered together with ART during acute infection. We believe this “window of opportunity” when the immune responses are still present and the latent reservoir is easier to reactivate will improve the efficacy of the “shock and kill HIV” approach to a cure. To address this, we will use GSK445A, a stabilized Ingenol-B based Protein Kinase C agonist (PKC) that we have shown can induce HIV/SIV transcription in vitro and in vivo in SIV-infected rhesus macaques (RM) on ART without significant toxicity. We propose to further optimize our strategy by evaluating if combining GSK445A with IL-15 can enhance the therapeutic effect. As such, the goal of this R01 is to determine whether administering this potent LRA during acute SIV infection, at the time of ART initiation, will delay or prevent viral rebound after ART cessation. The demonstration of therapeutic efficacy in this project will provide strong impetus for assessment of this concept in recently infected HIV+ individuals.

项目摘要 抗逆转录病毒治疗（ART）已显着改善与人类共同生活的人的预后， 免疫缺陷病毒（HIV）感染。然而，单独的ART不能根除感染，因此，每天 治疗必须终身维持，以防止不受控制的病毒复制复发和病毒感染的恢复。 疾病进展。不幸的是，除了与艾滋病毒感染有关的持续耻辱外， 治疗既给接受治疗的个人带来健康风险，也给社会带来重大经济负担。因此，在本发明中， 迫切需要开发能够治愈HIV感染的新的治疗干预。现在好了 确定在感染后的最初几天/几周内开始ART并不能阻止 长期存活的病毒库，虽然它是有效地减少其大小。另一项旨在减少 水库是诱导HIV基因表达的个人抑制性艺术的目标，消除潜伏 感染的细胞，这可能最终导致病毒根除。然而，清除艾滋病毒储存库不仅 需要通过潜伏期逆转剂（LRA）诱导病毒复制，但也需要消除这些 通过病毒致细胞病变效应或免疫细胞介导的杀伤作用重新激活潜伏感染的细胞， “震惊和杀戮”当LRA被施用给HIV感染者后，这种杀死通常是无效的。 几年的ART，可能是由于低水平抗原表达，LRA对清除的负面影响 有效的HIV特异性CD 8 + T细胞的低频率。在这里，我们建议评价一部小说， 在急性感染期间LRA与ART一起施用的策略。我们认为，这一“窗口” 当免疫反应仍然存在并且潜在的宿主更容易重新激活时，就会出现“机会”。 提高疗效的“休克和杀死艾滋病毒”的方法治愈。为了解决这个问题，我们将使用GSK 445 A， 我们已经证明，稳定的基于Ingenol-B的蛋白激酶C激动剂（PKC）可以诱导HIV/SIV转录 在体外和体内SIV感染的恒河猴（RM）ART没有显着的毒性。我们建议 通过评估GSK 445 A与IL-15的组合是否可以增强治疗效果来进一步优化我们的策略。 因此，该R 01的目标是确定在急性SIV感染期间给予这种强效LRA， 在开始抗逆转录病毒治疗时，将延迟或防止停止抗逆转录病毒治疗后的病毒反弹。的示范 该项目的治疗效果将为评估这一概念在最近感染的 艾滋病毒阳性者。