Reducing Latent Viral Reservoirs in Infant Macaques

减少幼年猕猴的潜在病毒库

• 批准号: 9283606
• 负责人: Nancy L Haigwood
• 金额: $ 121.53万
• 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/9283606
• 关键词: Abate; Acute; Address; Adult; Affect; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Birth; Blood; CD8-Positive T-Lymphocytes; 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; Immunity; Immunoglobulin G; Individual; Infant; Infection; Institutes; Latent Virus; Macaca; Macaca mulatta; Measurable; Mediating; Modeling; Mothers; Newborn Infant; Oral; Outcome; Passive Transfer of Immunity; Pathogenicity; Perinatal; Perinatal Infection; Pharmaceutical Preparations; Plasma; Play; Primates; Proviruses; Regimen; Research; Research Design; Research Priority; Research Proposals; Risk; Role; SIV; Satellite Viruses; Seminal; Speed; Suggestion; Therapeutic; Time; Tissues; Uncertainty; Viral; Viral Load result; Viral Pathogenesis; Viral load measurement; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Latency; Work; adaptive immune response; adaptive immunity; antiretroviral therapy; design; disorder prevention; exposure route; 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)：最近在实现艾滋病毒感染的功能性治愈方面的成功正在改变该领域的方向，以检查治疗方案以消除潜在的病毒库。抗逆转录病毒(ART)药物的鸡尾酒已经成功地将艾滋病毒+成年受试者的病毒血症降低到无法检测到的水平，这些受试者可以获得这种治疗。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。虽然抗逆转录病毒治疗是艾滋病毒+母亲及其婴儿在出生前、出生期间和出生后暴露于感染风险的标准护理，但该领域尚未解决可以减缓病毒扩张和消除已建立的潜在病毒库的抗逆转录病毒疗法的扩展。需要一种已证实的围产期感染的非人类灵长类动物模型，该模型检查可在感染时或感染后立即实施的新治疗方案，以解决是否有可能根除艾滋病毒。该项目的目标是采用已建立的新生恒河猴持续致病性SIV感染模型，以研究使用或不使用抗逆转录病毒疗法的早期治疗的效果。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灭菌免疫，当感染早期存在时，可以改变SIV或SIV感染的过程，稳定适应性免疫反应，防止病毒分化。旨在确定抗体对病毒库的影响程度的研究是该领域的下一步。这项研究建议的中心假设是，用有效的中和性人类单抗(NmAbs)进行治疗将导致艾滋病毒感染母亲所生婴儿中高度可控或无法检测到的病毒库。新生恒河猴口服感染SIV-SF162P3后，在最初的几个月内，血液和组织中会出现广泛分散和快速扩散的病毒准种 几天到几周的感染导致高度和持续的病毒血症。然而，在接受中和免疫球蛋白的被动治疗的新生猕猴中，疾病和死亡得到了预防，这表明在急性感染期间存在的NAB可以改变感染的动态，减少病毒的传播和宿主的建立。一旦确定了潜伏病毒库的时间和特征，该项目将确定NmAbb在(I)控制病毒载量、(Ii)影响整合病毒库的大小和(Iii)影响有效的适应性免疫反应的发展方面所发挥的作用。该项目还将研究单独使用时有效的NmAb鸡尾酒是否可以进一步增强抗逆转录病毒治疗的能力，从而更有效和持久地减少潜伏期。这项拟议研究的贡献预计将确定被动转移的中和抗体作为围产期疗法的优势，无论是单独使用还是与抗逆转录病毒疗法联合使用。