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病毒血症降低到HIV+无法检测到的水平 有能力访问它们并且可以坚持的成年受试者。但是，抑制性药物无法 消除细胞和组织室中的潜在病毒，因此需要继续缓解。 虽然艺术是艾滋病毒+母亲及其婴儿的护理标准，他们之前遇到感染风险，但 在出生后和出生后，无法在治疗后测试对病毒储层的影响 中断。我们已经开发了一种可重现的非人类灵长类动物（NHP）模型，用于传播 子宫，腹膜和母乳喂养，以检查新的治疗方案以进行预曝光 预防（PREP）或暴露后预防（PEP）。被动转移的BNAB可以提供消毒 当在非人类灵长类动物模型中用作PREP时的免疫力，最近也已证明 在病毒暴露的几天内将病毒储存物的建立为PEP。设计的研究 了解抗体的作用机理是至关重要的下一步。这项研究的中心假设 提案是针对艺术，CCR5阻滞抗体和有效的新型，正交治疗的新型，正交治疗 中和人类单克隆抗体（BNAB）将导致高度控制的病毒血症和无法检测到的 艾滋病毒感染的母亲出生的婴儿中的病毒储藏。感染时新生儿和婴儿恒河猕猴 口服SHIVSF1623在血液和 在感染的最初几天内组织，导致高和持续的病毒血症。但是，在 在暴露后24-30小时接收艺术或bnabs的新生猕猴，永久性病毒播种是 阻止了治疗的延迟导致治疗停止后反弹。该项目将探索 与ART，LERONLIMAB和BNABS结合和顺序处理的影响，我们预测这将导致 在预防病毒储层时，用作预防，并减少或消除病毒 病毒暴露后的头几周用作PEP时的储层。我们将显示减少的影响 通过正电子发射断层扫描的体内成像传染中心，并将这些结果与 标准病毒学测定和rnascope成像。最终，我们希望这种组合疗法将领导 转化为诊所，以便可以治疗受HIV暴露和垂直感染的婴儿 时间和经历耐用的病毒缓解，无需进一步治疗。