Targeting the HIV/SIV reservoir at time of ART initiation

在开始 ART 时针对 HIV/SIV 病毒库

基本信息

批准号：
10101853
负责人：
Afamefuna Okoye
金额：
$ 68.79万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10101853
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 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 outcome forecast prevent purge simian human immunodeficiency virus social stigma success treatment effect viral rebound

项目摘要

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.

项目概要抗逆转录病毒疗法（ART）显着改善了人类携带者的预后然而，仅靠 ART 无法根除感染，因此每天都需要进行治疗。必须终生维持治疗，以防止不受控制的病毒复制复发和恢复不幸的是，除了与艾滋病毒感染相关的持续耻辱之外，疾病的进展也会伴随终生。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。迫切需要开发能够治愈艾滋病毒感染的新型治疗干预措施。确定在感染后的头几天/几周内开始 ART 并不能阻止建立长寿命的病毒库，尽管它可以有效地减少其大小。储存库的目的是在接受抑制性 ART 的个体中诱导 HIV 基因表达，目的是消除潜伏病毒被感染的细胞，这最终可能导致病毒被根除，然而，这不仅清除了艾滋病毒储存库。需要通过潜伏期逆转剂（LRA）诱导病毒复制，但也需要消除这些病毒通过病毒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，即所谓的当对艾滋病毒感染者使用上帝抵抗军时，这种杀戮通常是低效的。数年的 ART，可能是由于抗原表达水平低、LRA 对清除的负面影响机制或有效的 HIV 特异性 CD8+ T 细胞的低频率在这里我们建议评估一种新型的。我们相信这种“窗口期”是在急性感染期间将 LRA 与 ART 一起使用的策略。当免疫反应仍然存在并且潜在的储存库更容易重新激活时，“机会” 提高“休克并杀死 HIV”疗法的功效为了解决这个问题，我们将使用 GSK445A，一种我们已经证明基于稳定的巨大戟醇-B 的蛋白激酶 C 激动剂 (PKC) 可以诱导 HIV/SIV 转录我们建议，在感染 SIV 的恒河猴 (RM) 中进行 ART 的体外和体内实验，没有明显的毒性。通过评估GSK445A与IL-15联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 R01 的目标是确定在急性 SIV 感染期间是否施用这种有效的 LRA，在 ART 开始时，将延迟或防止 ART 停止后病毒反弹。该项目的治疗效果将为评估最近感染的这一概念提供强大的推动力 HIV+ 个体。