Reducing Latent Viral Reservoirs in Infant Macaques

减少幼年猕猴的潜在病毒库

• 批准号: 10155511
• 负责人: Nancy L Haigwood
• 金额: $ 85.88万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10155511
• 关键词: Acute; Address; Adult; Affect; Aftercare; Animal Model; Anti-Retroviral Agents; Antibodies; Antibody Therapy; Biodistribution; Biological Assay; Birth; Blocking Antibodies; Blood; Breast Feeding; CCR5 gene; Cells; Child; Clinic; Clinical; Combined Modality Therapy; Disease remission; Dose; Exposure to; Goals; Grant; HIV; HIV-1; Health; Hour; Human; Image; Immunity; Infant; Infection; Interruption; Length; Macaca; Macaca mulatta; Maternal antibody; Maternal-Fetal Transmission; Memory; Modality; Modeling; Monitor; Monoclonal Antibodies; Mothers; Newborn Infant; Oral; Pathogenicity; Perinatal; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Prevention; Primates; Prophylactic treatment; Regimen; Reproducibility; Research Design; Research Proposals; Residual state; Risk; Route; Safety; Satellite Viruses; Sequential Treatment; Severity of illness; Testing; Therapeutic; Therapeutic antibodies; Time; Tissues; Translations; Vertical Disease Transmission; Viral; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Latency; Withholding Treatment; Work; antibody engineering; design; experience; experimental study; human monoclonal antibodies; in utero; in vivo imaging; infant infection; infection risk; insight; mother nutrition; neutralizing monoclonal antibodies; nonhuman primate; novel; novel strategies; novel therapeutics; pandemic disease; pediatric human immunodeficiency virus; pre-exposure prophylaxis; prevent; prophylactic; research clinical testing; simian human immunodeficiency virus; standard of care; subcutaneous; therapeutic effectiveness; therapy development; viral rebound; virology

PROJECT SUMMARY Cocktails of antiretroviral drugs (ART) have been successful in reducing viremia to undetectable levels in HIV+ adult subjects who have access to them and who can remain adherent. Yet, the suppressive drugs are unable to eliminate latent virus in cellular and tissue compartments and are thus required for continued remission. While ART is the standard of care for HIV+ mothers and their infants who are exposed to infection risk before, during, and after birth, it has not been possible to test the impact on viral reservoirs upon treatment interruption. We have developed a robust, reproducible nonhuman primate (NHP) model for transmission in utero, peripartum and breastfeeding, in order to examine new therapeutic regimens for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Passively transferred bNAbs can provide sterilizing immunity when used as PrEP in nonhuman primate models, and have also been recently shown to prevent the establishment of viral reservoirs when given as PEP within days of viral exposure. Studies designed to understand the mechanism of action of antibodies is a critical next step. The central hypothesis of this research proposal is that novel, orthogonal therapeutic treatment with ART, a CCR5-blocking antibody, and potent neutralizing human monoclonal antibodies (bNAbs) will result in highly controlled viremia and undetectable viral reservoirs in babies born to HIV-infected mothers. Newborn and infant rhesus macaques when infected orally with SHIVSF162P3 develop widely dispersed and rapidly diverging viral quasispecies in blood and tissues within the first few days to weeks of infection, resulting in high and persistent viremia. However, in newborn macaques that receive ART or bNAbs at 24-30 hours after exposure, permanent viral seeding is prevented, but delays in treatment result in rebound upon treatment cessation. The project will explore the effects of combination and sequential treatment with ART, Leronlimab, and bNAbs, which we predict will result in prevention of viral reservoir establishment when used as PrEP, and in reduction or elimination of viral reservoirs when used as PEP in the first few weeks after virus exposure. We will show the effects of reduced infectious centers by in vivo imaging with positron emission tomography and compare these results with standard virological assays and RNAscope imaging. Ulimately, we hope that this combination therapy will lead to translation into the clinic so that HIV-exposed and vertically infected babies can be treated for limited periods of time and experience durable viral remission without further treatment.

项目摘要 抗逆转录病毒药物（ART）的鸡尾酒已成功地将HIV+患者的病毒血症降低到无法检测的水平。 能够接触到这些药物并能够保持依从性的成人受试者。然而，抑制性药物无法 以消除细胞和组织区室中的潜伏病毒，因此需要持续缓解。 虽然抗逆转录病毒疗法是对以前有感染风险的艾滋病毒阳性母亲及其婴儿的标准护理， 在出生期间和出生后，尚不可能测试治疗对病毒储库的影响 中断.我们已经开发了一个强大的，可重复的非人灵长类动物（NHP）模型，用于在 子宫内、围产期和哺乳期，以检查暴露前的新治疗方案 预防（PrEP）或暴露后预防（PEP）。被动转移的bNAb可以提供灭菌 在非人灵长类动物模型中用作PrEP时， 在病毒暴露的几天内以PEP形式给药时建立病毒储存库。研究旨在 了解抗体的作用机制是下一步的关键。这项研究的核心假设是 该提议是使用ART（一种CCR 5阻断抗体）和强效ART进行新型、正交治疗 中和人单克隆抗体（bNAb）将导致高度控制的病毒血症， 艾滋病毒感染母亲所生婴儿的病毒宿主。新生儿和婴儿恒河猴感染时 口服SHIVSF 162 P3在血液中产生广泛分散和迅速分化的病毒准种， 在感染的最初几天到几周内，病毒会感染组织，导致高水平和持续的病毒血症。但在 在暴露后24-30小时接受ART或bNAb的新生猕猴中， 预防，但治疗延迟导致治疗停止后反弹。该项目将探讨 ART、Leronlimab和bNAbs联合和序贯治疗的效果，我们预测将导致 当用作PrEP时，在预防病毒储库建立中，以及在减少或消除病毒感染中， 在病毒暴露后的最初几周内用作PEP时，我们将展示减少 感染中心的体内成像与正电子发射断层扫描和比较这些结果与 标准病毒学测定和RNA显微镜成像。ulibrium，我们希望这种联合疗法将导致 将其转化为诊所，以便接触艾滋病毒和垂直感染的婴儿可以在有限的时间内得到治疗， 并经历持久的病毒缓解而无需进一步治疗。