Reducing Latent Viral Reservoirs in Infant Macaques

减少幼年猕猴的潜在病毒库

• 批准号: 8728687
• 负责人: Nancy L Haigwood
• 金额: $ 94.19万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728687
• 关键词: Abate; Acute; Address; Adult; Affect; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Birth; Blood; CD8B1 gene; Cells; Cessation of life; Characteristics; Clinic; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease Outcome; Dose; Early treatment; Epitopes; Exposure to; Goals; HIV; HIV Infections; HIV-1; Human; Immune response; Immunity; Immunoglobulin G; Individual; Infant; Infection; Institutes; Latent Virus; Left; Life; Macaca; Macaca mulatta; Measurable; Mediating; Modeling; Mothers; Newborn Infant; Oral; Outcome; Perinatal; Perinatal Infection; Pharmaceutical Preparations; Plasma; Play; Primates; Proviruses; Regimen; Research; Research Design; Research Priority; Research Proposals; Risk; Role; Route; SIV; Satellite Viruses; Seminal; Speed; Suggestion; T-Lymphocyte; Therapeutic; Time; Tissues; Uncertainty; Viral; Viral Load result; Viral Pathogenesis; Viral load measurement; Viremia; Virus; Virus Diseases; Work; adaptive immunity; antiretroviral therapy; base; design; disorder prevention; human monoclonal antibodies; insight; neutralizing antibody; nonhuman primate; novel strategies; novel therapeutics; pandemic disease; prevent; public health relevance; response; simian human immunodeficiency virus; standard of care; success; transmission process

DESCRIPTION (provided by applicant): Recent successes in achieving a functional cure for HIV infection are redirecting the field to examine therapeutic regimens to eliminate latent virus reservoirs. Cocktails of antiretroviral (ART) drugs have been successful in reducing viremia to undetectable levels in HIV+ adult subjects that have access to the therapy. Yet, the drugs are unable to eliminate latent virus in certain cellular and tissue compartments. While ART is the standard of care for HIV+ mothers and their infants who are exposed to infection risk before, during, and after birth, the field has not addressed an extension of ART therapy that could abate virus expansion and eliminate established latent viral reservoirs. A proven nonhuman primate model for perinatal infection that examines new therapeutic regimens that can be instituted at or immediately following infection is needed to address whether it is possible to eradicate HIV. The objective of the proposed project is to adapt an established model of persistent pathogenic SHIV infection in newborn rhesus macaques to study the effects of very early therapies with or without ART. Understanding the full contribution of antibodies, including neutralizing antibodies (NAbs), in HIV-1 infection remains one of the highest research priorities. Passively transferred NAbs can provide sterilizing immunity in nonhuman primate models and when present early in infection can change the course of SIV or SHIV infection stabilizing the adaptive immune response to prevent viral divergence. Studies designed to define how well antibodies can affect the viral reservoir are the next steps in the field. The central hypothesis of this research proposal is that therapeutic treatment with potent neutralizing human monoclonal antibodies (NmAbs) will result in highly controlled or undetectable viral reservoirs in babies born to HIV-infected mothers. Newborn rhesus macaques when infected orally with SHIV-SF162P3 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 passive treatment with neutralizing IgG, disease and death is prevented demonstrating that NAbs present during acute infection can alter the dynamics of infection and reduce viral spread and establishment of the reservoir. Once the timing and characterization of latent viral pools are characterized, the project will define the roles that NmAbs play in (i) controlling virus load, (ii) affecting the size of the integrated viral reservoir, and (iii) influecing the development of effective adaptive immune responses. The project will also examine whether NmAb cocktails that are effective when used alone can further augment the ability of ART resulting in more potent and durable reduction in latency. The contribution of the proposed research is expected to define the advantage of passively transferred neutralizing antibodies as therapeutics in a perinatal setting either alone or in concert with ART.

描述（由申请人提供）：最近在实现HIV感染的功能性治愈方面取得的成功将该领域重新定向到检查治疗方案以消除潜伏的病毒库。抗逆转录病毒药物的鸡尾酒疗法已经成功地将艾滋病毒阳性成人受试者体内的病毒血症降低到无法检测到的水平。然而，这些药物无法消除某些细胞和组织隔间中的潜伏病毒。虽然抗逆转录病毒疗法是艾滋病毒阳性母亲及其婴儿在出生前、出生期间和出生后面临感染风险的标准护理方法，但该领域尚未解决延长抗逆转录病毒疗法的问题，以减少病毒增殖并消除已建立的潜伏病毒库。需要一个经过验证的围产期感染的非人类灵长类动物模型来检验在感染时或感染后立即建立的新治疗方案，以解决是否有可能根除艾滋病毒。拟议项目的目标是调整新生恒河猴持续致病性SHIV感染的既定模型，以研究使用或不使用ART的非常早期治疗的效果。了解抗体，包括中和抗体（nab）在HIV-1感染中的全部作用仍然是最高的研究重点之一。被动转移的nab可以在非人灵长类动物模型中提供绝育免疫，并且在感染早期存在时可以改变SIV或SHIV感染的过程，稳定适应性免疫反应以防止病毒分化。旨在确定抗体对病毒库影响程度的研究是该领域的下一步工作。本研究建议的中心假设是，使用强效中和性人单克隆抗体（nmab）进行治疗将导致hiv感染母亲所生婴儿的病毒库高度控制或无法检测到。新生恒河猴经口感染SHIV-SF162P3后，在最初的几分钟内就会在血液和组织中形成广泛分散和迅速分化的病毒准种