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.

项目总结 抗逆转录病毒药物的鸡尾酒疗法(ART)已成功地将HIV+病毒血症降低到检测不到的水平。 成年受试者，他们可以接触到这些文件，并可以保持追随者。然而，抑制性药物却无法 以消除细胞和组织间隔中的潜伏病毒，因此需要继续缓解。 虽然抗逆转录病毒治疗是以前接触感染风险的艾滋病毒+母亲及其婴儿的护理标准， 在出生期间和出生后，还不可能测试治疗后对病毒库的影响 中断。我们开发了一种健壮的、可重复的非人灵长类动物(NHP)模型，用于在 子宫、围产期和母乳喂养，以研究新的暴露前治疗方案 预防(PrEP)或暴露后预防(PEP)。被动转移的bNAbs可以提供杀菌作用 免疫在非人灵长类动物模型中用作PrEP时，最近也被证明可以防止 在病毒暴露几天内以PEP的形式给予时，建立病毒库。研究旨在 了解抗体的作用机制是关键的下一步。这项研究的中心假设是 建议用ART，一种阻断CCR5的抗体，有效的，新颖的，正交的治疗方法 中和人类单抗(BNAbs)会导致高度可控的病毒血症，并且无法检测到 艾滋病毒感染母亲所生婴儿中的病毒蓄积者。新生儿和婴儿感染恒河猴时 口服SHIVSF162P3会在血液和血液中产生广泛分散和快速分散的病毒准种 组织在感染的最初几天到几周内，导致高度和持续的病毒血症。但是，在 在暴露后24-30小时接受ART或bNAbs的新生猕猴，永久病毒播种是 预防，但治疗延迟会导致治疗停止后反弹。该项目将探索 ART、Leronlimab和bNAbs联合和序贯治疗的效果，我们预测结果是 在用作PrEP时防止病毒库的建立，以及在减少或消除病毒方面 在病毒暴露后的头几个星期，当病毒被用作PEP时，储藏者会被感染。我们将展示减少的影响 用正电子发射断层扫描进行体内成像，并将这些结果与 标准病毒学分析和RNAScope成像。最终，我们希望这种联合疗法将导致 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接受治疗 时间和经历持久的病毒缓解，而不需要进一步治疗。