Reducing Latent Viral Reservoirs in Infant Macaques

减少幼年猕猴的潜在病毒库

• 批准号: 10441140
• 负责人: Nancy L Haigwood
• 金额: $ 85.75万
• 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/10441140
• 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

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.

项目概要 抗逆转录病毒药物 (ART) 混合物已成功将 HIV+ 患者的病毒血症降低至检测不到的水平 能够接触到这些内容并且能够保持坚持的成年受试者。然而，抑制药物却无法 消除细胞和组织区室中的潜伏病毒，因此是持续缓解所必需的。 虽然 ART 是 HIV 阳性母亲及其婴儿的标准护理方法，但她们之前曾面临感染风险， 出生期间和出生后，尚无法测试治疗对病毒库的影响 中断。我们开发了一种稳健、可重复的非人类灵长类动物 (NHP) 模型，用于在 子宫内、围产期和母乳喂养，以检查新的暴露前治疗方案 预防（PrEP）或暴露后预防（PEP）。被动转移的 bNAb 可提供灭菌作用 在非人类灵长类动物模型中用作 PrEP 时可产生免疫力，并且最近也被证明可以预防 在病毒暴露后几天内作为 PEP 给予，病毒库就会建立。研究旨在 了解抗体的作用机制是下一步的关键。本研究的中心假设 建议采用 ART（一种 CCR5 阻断抗体）和有效的新型正交治疗方法 中和人单克隆抗体 (bNAb) 将导致高度控制的病毒血症且无法检测到 感染艾滋病毒的母亲所生婴儿的病毒储存库。新生儿和幼年恒河猴感染时 口服 SHIVSF162P3 在血液和血液中形成广泛分散且快速分化的病毒准种 在感染的最初几天到几周内，组织中的病毒被破坏，导致高且持续的病毒血症。然而，在 在暴露后 24-30 小时内接受 ART 或 bNAb 的新生猕猴，永久病毒播种是 可以预防，但延迟治疗会导致治疗停止后反弹。该项目将探索 我们预测 ART、Leronlimab 和 bNAb 联合治疗和序贯治疗的效果 用作 PrEP 时可预防病毒储存库的建立，并可减少或消除病毒 在病毒暴露后的最初几周内用作 PEP 的储存库。我们将展示减少的效果 通过正电子发射断层扫描体内成像对感染中心进行分析，并将这些结果与 标准病毒学检测和 RNAscope 成像。最终，我们希望这种联合疗法能够引领 转移到诊所，以便艾滋病毒暴露和垂直感染的婴儿可以在有限的时间内得到治疗 并在无需进一步治疗的情况下获得持久的病毒缓解。