Early intervention with anti-proliferative therapy close to ART initiation to limit long-term SIV persistence

在 ART 开始时进行早期抗增殖治疗干预，以限制 SIV 的长期持续存在

基本信息

批准号：
10849960
负责人：
Joseph Christopher Mudd
金额：
$ 90.9万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10849960
关键词：
Acquired Immunodeficiency Syndrome Acute Animal Model Animals Antigens Autologous Binding Blood specimen CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cell Culture Techniques Cell Proliferation Cells Clonality Clone Cells Combined Modality Therapy DNA Dasatinib Deuterium Deuterium Oxide Dose Drug Combinations Drug Screening Early Intervention FDA approved HIV HIV Infections HIV-1 Half-Life Human IL7 gene Immune response Immune system Immunologic Memory Immunosuppression Individual Infection Interruption Label Libraries Lymphocyte Lymphopenia Macaca Macaca mulatta Measures Molecular Monitor Organ Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Plasma Play Population Primary Infection Proliferating Proviruses Recovery Regimen Reporting Role SIV Safety Serum Source Structure T-Cell Depletion T-Cell Proliferation T-Lymphocyte Subsets Testing Therapeutic Therapeutic Effect Thymidine Kinase Time Tissues Toxic effect Viral Viral Proteins Virus Virus Diseases Water antiproliferative agents antiretroviral therapy chemotherapeutic agent immunoregulation in vitro testing in vivo integration site kinase inhibitor leukemia mathematical model mycophenolate mofetil pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics pharmacologic pre-clinical response targeted agent viral rebound

项目摘要

PROJECT 1 SUMMARY HIV persists despite decades of antiretroviral therapy (ART) because of a population of latently infected CD4+ T cells known as the HIV reservoir. The HIV reservoir is sustained by proliferation of infected CD4+ T cells, which do not express enough viral protein to be eliminated by HIV-specific immune responses. While proliferation of cells is a promising target for curing HIV and eliminating the need for lifelong ART, a comprehensive preclinical structure to develop a lymphocyte anti-proliferation therapeutic strategy does not exist. Recent evidence suggests that CD4+ T cell proliferation plays a vital role in generating multiple proliferative clones of latently infected cells extremely early during untreated HIV infection. We developed a mathematical model which suggests that massive CD4+ T cell proliferation coincident with recovery from CD4+ lymphopenia, occurs during weeks 1-4 of primary HIV infection and is vital for generating much of the HIV reservoir. We hypothesize that effective anti-proliferative (AP) therapy given during this critical three-week window will limit the volume and alter the clonal structure of the HIV reservoir. In Aim 1 of this application, Dr. Adam Spivak will test small molecular agents targeting CD4+ T cell proliferation given alone and in combination. A comprehensive library of immunomodulatory and chemotherapeutic agents with high therapeutic potential will be tested for their AP effects ex vivo on CD4+ T cell cultures, ex vivo on latently HIV-1 infected cells derived from human donors, and in vivo in uninfected rhesus macaques by measuring impact on CD4+ T cell turnover using deuterium water labeling. Finally, Dr. Joshua Schiffer will utilize mathematical models which capture drug pharmacokinetics and pharmacodynamics, as well as the underlying dynamics of CD4+ T cell subsets within the HIV reservoir, to optimize selection of single drug or combination anti-proliferative (AP) regimens for dosing of SIV infected animals in Aim 2. In Aim 2, Dr. Joseph Mudd will evaluate the effects of optimized AP agents on early reservoir formation dynamics in 24 SIV-infected rhesus macaques: 6 will receive ART alone between weeks 1-25 post infection; 6 will receive ART alone between weeks 4-28 post infection; 6 will receive ART between weeks 1-25 and optimized AP therapy between weeks 1-4 post infection; 6 will receive ART between weeks 4-28 and optimized AP therapy between weeks 1-4 post infection. Optimized AP regimens will be selected from Aim 1. During ART, we will measure the in vivo AP therapeutic effect on 1) SIV reservoir volume with total and intact SIV DNA, 2) reservoir CD4+ T cell subset composition, 3) in vivo CD4+ T cell turnover with D2O labeling, and 4) SIV reservoir clonal structure using integration site sequencing, based on frequent longitudinal sampling of blood and gut tissues. After 24 weeks of ART, we will stop ART and monitor viral rebound for up to 4 months. We hypothesize that AP therapy between weeks 1 and 4 post infection will reduce total and intact SIV DNA and decrease reservoir clonality following 6 months of ART, and increase time to SIV rebound after ART interruption.

项目 1 摘要尽管进行了数十年的抗逆转录病毒治疗 (ART)，但由于潜伏感染的 CD4+ 人群，艾滋病毒仍然存在 T 细胞被称为 HIV 储存库。 HIV 储存库是通过受感染的 CD4+ T 细胞的增殖来维持的，没有表达足够的病毒蛋白来被 HIV 特异性免疫反应消除。虽然扩散细胞是治愈 HIV 并消除终生 ART 需求的有希望的目标，这是一种全面的临床前治疗开发淋巴细胞抗增殖治疗策略的结构并不存在。最近的证据表明 CD4+ T 细胞增殖在产生多种增殖细胞中起着至关重要的作用。在未经治疗的艾滋病毒感染期间极早期潜伏感染细胞的克隆。我们开发了一个数学该模型表明大量 CD4+ T 细胞增殖与 CD4+ 淋巴细胞减少症的恢复同时发生，发生在 HIV 原发感染的第 1-4 周，对于产生大部分 HIV 病毒库至关重要。我们假设在这个关键的三周窗口期给予有效的抗增殖（AP）治疗将限制体积并改变 HIV 储存库的克隆结构。在本申请的目标 1 中，Adam Spivak 博士将测试针对 CD4+ T 细胞的小分子药物单独或组合地进行增殖。免疫调节和免疫调节综合库将测试具有高治疗潜力的化疗药物对 CD4+ T 细胞的离体 AP 效应体外培养来自人类捐赠者的潜伏 HIV-1 感染细胞，以及体内未感染的恒河猴通过使用氘水标记测量对 CD4+ T 细胞更新的影响来对猕猴进行研究。最后，约书亚博士 Schiffer 将利用数学模型来捕捉药物药代动力学和药效学作为 HIV 储存库内 CD4+ T 细胞亚群的潜在动态，以优化单一药物的选择或联合抗增殖 (AP) 方案，用于目标 2 中 SIV 感染动物的给药。在目标 2 中，Joseph Mudd 博士将评估优化的 AP 剂对早期储层形成的影响 24 只感染 SIV 的恒河猴的动态：其中 6 只将在感染后 1-25 周内单独接受 ART； 6 将在感染后 4-28 周内单独接受 ART； 6 人将在第 1-25 周期间接受 ART 并进行优化感染后 1-4 周进行 AP 治疗； 6 人将在第 4-28 周期间接受 ART 和优化 AP 治疗感染后 1-4 周之间。将从目标 1 中选择优化的 AP 方案。在 ART 期间，我们将测量体内 AP 对 1) SIV 储库体积的治疗效果，包括总体积和完整的 SIV DNA，2) 储存库 CD4+ T 细胞亚群组成，3) D2O 标记的体内 CD4+ T 细胞周转， 4) 基于频繁纵向采样，使用整合位点测序的 SIV 储库克隆结构血液和肠道组织。 ART 24 周后，我们将停止 ART 并监测病毒反弹长达 4 个月。我们假设感染后第 1 周至第 4 周之间的 AP 治疗将减少总的和完整的 SIV DNA，并且 ART 6 个月后，降低了储存库克隆性，并增加了 ART 中断后 SIV 反弹的时间。