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: 10222532
• 负责人: Afamefuna Okoye
• 金额: $ 69.66万
• 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/10222532
• 关键词: Acute; Address; Agonist; Alleles; Antigens; Antiviral Agents; 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; 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.

项目总结 抗逆转录病毒疗法(Art)极大地改善了与人类生活在一起的人的预后。 免疫缺陷病毒(HIV)感染。然而，单靠抗逆转录病毒治疗不能根除这种感染，因此，每天 必须终生维持治疗，以防止病毒不受控制的复制和恢复 疾病的发展。不幸的是，除了与艾滋病毒感染相关的持久耻辱之外，终身 治疗既会给接受治疗的个人带来健康风险，也会给社会带来巨大的经济负担。因此， 迫切需要开发能够治愈艾滋病毒感染的新的治疗干预措施。现在已经很好了 确定在感染后的头几天/几周内开始抗逆转录病毒治疗并不妨碍建立 长寿的病毒库，尽管它在缩小其大小方面是有效的。另一项旨在减少 蓄水池是通过抑制ART诱导个体的HIV基因表达，目的是消除潜伏期 被感染的细胞，这最终可能导致病毒根除。然而，清除艾滋病毒储藏者不仅 需要通过潜伏期反转剂(LRA)诱导病毒复制，但也需要消除这些 通过病毒的细胞病变效应或免疫细胞介导的杀伤重新激活潜伏感染的细胞，即所谓的 “电击和杀戮”。当LRA被注射到HIV感染者身上时，这种杀戮通常是无效的 几年的抗逆转录病毒治疗，可能是由于低水平的抗原表达，LRAs对清除的负面影响 有效的HIV特异性CD8+T细胞的机制或低频率。在这里，我们建议评估一部小说 在急性感染期间，LRA与ART一起使用的策略。我们相信这扇“窗口” 当免疫反应仍然存在，潜伏的储存库更容易重新激活时，机会将 提高“震慑和杀死艾滋病毒”治愈方法的疗效。为了解决这个问题，我们将使用GSK445A，一个 我们已经证明的稳定的基于吲哚-B的蛋白激酶C激动剂(PKC)可以诱导HIV/SIV转录 在体内外，SIV感染恒河猴(RM)对ART均无明显毒性。我们建议 进一步优化我们的策略，评估GSK445A和IL-15联合使用是否可以提高治疗效果。 因此，R01的目标是确定在急性SIV感染期间是否使用这种有效的LRA， 在ART开始时，将延迟或防止ART停止后病毒反弹。演示了 该项目的治疗效果将为评估这一概念在最近感染的患者中提供强大的推动力。 HIV+的个人。