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Reducing Latent Viral Reservoirs in Infant Macaques

减少幼年猕猴的潜在病毒库

基本信息

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
项目类别：
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

项目摘要

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