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：
8901254
负责人：
Nancy L Haigwood
金额：
$ 119.45万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901254
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 Health Human 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 response simian human immunodeficiency virus standard of care success transmission process

项目摘要

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）：在实现HIV感染功能治疗方面取得的最新成功正在重定向领域检查治疗方案以消除潜在的病毒储量。抗逆转录病毒（ART）药物的鸡尾酒已成功地将病毒血症降低到可以使用该治疗的HIV+成人受试者中无法检测到的水平。然而，这些药物无法消除某些细胞和组织室中的潜在病毒。尽管艺术是在出生之前，之中和出生后暴露于感染风险的艾滋病毒+母亲及其婴儿的护理标准，但该领域尚未解决艺术疗法的扩展，该疗法可以减轻病毒的扩张并消除已建立的潜在病毒储量。围产期感染的一种经过验证的非人类灵长类动物模型，研究了可以在感染后或在感染后立即建立的新治疗方案，以解决是否可以消除HIV。拟议项目的目的是适应新生儿猕猴中持续的致病性SHIV感染模型，以研究有或没有ART的早期疗法的影响。在HIV-1感染中了解抗体的全部贡献，包括中和抗体（NABS），仍然是最高的研究优先事项之一。被动转移的NAB可以在非人类灵长类动物模型中提供消毒免疫力，而在感染早期就存在时可以改变SIV或SHIV感染的过程，从而稳定适应性免疫反应以防止病毒发散。旨在定义抗体如何影响病毒储层的研究是该领域的下一步。该研究提案的中心假设是，用有效的中和人类单克隆抗体（NMAB）的治疗治疗将导致受HIV感染的母亲出生的婴儿高度控制或无法检测到的病毒储量。新生儿猕猴用SHIV-SF162P3口服感染时，在前几个的血液和组织中，血液和组织中的病毒式形成广泛分散并迅速分歧感染的天数到几周，导致高和持续的病毒血症。但是，在接受中和IgG接受被动治疗的新生猕猴中，疾病和死亡是阻止疾病和死亡的，表明急性感染期间存在的NAB可以改变感染的动力学，并减少储层的病毒传播和建立。一旦表征了潜在病毒池的时间和表征，该项目将定义NMAB在控制病毒载荷中所起的作用，（ii）影响综合病毒储层的大小，以及（iii）影响有效适应性免疫反应的发展。该项目还将检查单独使用时有效的NMAB鸡尾酒是否可以进一步增强艺术的能力，从而导致延迟的有效和持久性。预计拟议的研究的贡献将定义一个单独或与ART共同进行的围产期环境中被动转移的中和抗体作为治疗剂的优势。