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HIV感染的功能性治愈方面的成功正在将该领域重新定向到研究消除潜伏病毒储库的治疗方案。抗逆转录病毒（ART）药物的鸡尾酒已成功地减少病毒血症到无法检测到的水平，在艾滋病毒+成人受试者有机会获得治疗。 然而，这些药物无法消除某些细胞和组织隔室中的潜伏病毒。虽然ART是HIV阳性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ART治疗的扩展，该扩展可以减少病毒扩增并消除已建立的潜伏病毒储库。需要一个经证实的非人灵长类动物围产期感染模型，检查新的治疗方案，可以在感染时或感染后立即制定，以解决是否有可能根除艾滋病毒。 拟议项目的目的是适应一个建立的模型，持续致病性SHIV感染的新生恒河猴研究的影响，非常早期的治疗与或不ART。了解抗体，包括中和抗体（NAB），在HIV-1感染的全部贡献仍然是最高的研究优先事项之一。被动转移的NAb可以在非人灵长类动物模型中提供杀菌免疫，并且当在感染早期存在时，可以改变SIV或SHIV感染的过程，稳定适应性免疫应答以防止病毒趋异。 旨在确定抗体如何影响病毒库的研究是该领域的下一步。这项研究建议的中心假设是，使用强效中和人单克隆抗体（NmAbs）进行治疗性治疗将导致HIV感染母亲所生婴儿的病毒库高度受控或无法检测。 当用SHIV-SF 162 P3口服感染新生恒河猴时，在最初的几个月内， 数天至数周的感染，导致高和持续的病毒血症。然而，在接受中和IgG被动治疗的新生猕猴中，预防了疾病和死亡，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病毒传播和储库的建立。一旦潜伏病毒库的时间和特征得到表征，该项目将定义NmAbs在以下方面发挥的作用：（i）控制病毒载量，（ii）影响整合病毒库的大小，以及（iii）影响有效适应性免疫应答的发展。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ART的能力，从而更有效和持久地减少潜伏期。预计拟议研究的贡献将确定被动转移中和抗体作为围产期治疗药物的优势，无论是单独治疗还是与ART联合治疗。