AAV-Delivered Broadly Neutralizing Antibodies for HIV Suppression

AAV 传递的广泛中和抗体可抑制 HIV

基本信息

批准号：
10221805
负责人：
Matthew Ryan Gardner
金额：
$ 24.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-16 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221805
关键词：
Address Advisory Committees Anti-Retroviral Agents Antibodies Antibody Response Binding Sites Biological Biological Availability Biophysics Capsid Clinical Clinical Trials DNA cassette Dependovirus Development Dose Epitopes Evolution Foundations Future Gene Transduction Agent Glycoproteins Goals Grant HIV HIV Antibodies HIV Entry Inhibitors HIV-1 Human Individual Infection Infusion procedures Intramuscular Intravenous Life Lifting Liver Lymphoid Tissue Macaca Macaca mulatta Measures Mediating Mentors Monitor Mucous Membrane Mus Muscle Patients Peptides Pharmaceutical Preparations Pharmacotherapy Phase Plasma Property Reporting Research Research Personnel Resistance Resources SIV Science Solubility System Technology Testing Therapeutic Training Treatment Efficacy Variant Viral Viral Load result Viremia Virus Virus Diseases Virus Replication Work World Health Organization Writing adeno-associated viral vector antiretroviral therapy base collaborative environment experience human disease humanized mouse immunogenic immunogenicity improved insight neutralizing antibody nonhuman primate novel prevent programs promoter receptor side effect simian human immunodeficiency virus skills transgene expression vector viral DNA viral RNA viral rebound

项目摘要

PROJECT SUMMARY The 2015 UNAIDS report estimates that over 35 million people are infected with HIV. Despite the lack of a sterilizing cure, antiretroviral drug therapies (ART) effectively suppress viral replication in infected individuals. However, only 17 million infected individuals have access to ART. Additionally, ART is a life-long therapy that requires daily administration and is associated with a range of unwanted side effects. Broadly neutralizing antibodies (bNAbs) may be able to supplement or replace ART. Several such antibodies have already shown promise in human clinical trials, where a single dose can decrease viremia in HIV-1 infected individuals. However, viral rebound occurs rapidly during treatment as the bNAb concentration decreases and resistant variants are selected. Adeno-associated virus (AAV) vectors can express bNAbs for years at concentrations capable of limiting viral evolution and maintaining viral suppression. However, we and other groups have shown the emergence of anti-drug antibodies (ADA) to expressed bNAbs that can limit their expression. In this K99/R00 proposal, I will address three key questions associated with the use of AAV-delivered bNAbs in a functional cure. 1) Which bNAbs have biophysical and neutralization properties consistent with suppressing an established infection? 2) Can vector and AAV capsid optimization increase bNAb expression and help limit the host ADA response? 3) Can AAV-delivered bNAbs suppress an established SHIV infection in rhesus macaques, obviating the need for ART? By answering these questions, we will determine how best to use AAV vectors to treat an AAV infection, and provide insight for investigators using AAV in other clinical contexts. My research with AAV and HIV-1 systems and my development of non-human primate projects as a Ruth L. Kirschstein Fellow have provided me with the training necessary to complete these aims. TSRI provides an outstanding research environment for collaborative science, especially in the HIV field. Moreover, I will attend courses offered at TSRI and Cold Spring Harbor that will provide further training on becoming an independent investigator. My mentor, Dr. Farzan, along with my Scientific Advisory Committee consisting of Drs. Ron Desrosiers, Susana Valente and Hyeryun Choe, are committed to providing me with an excellent training in developing my research goals and improving my grant writing skills for future R01 submissions. The skills I acquire during the training phase will serve as a foundation for my own research program during the independent phase, with the specific goals of developing new gene-therapy vectors and applying these vectors to human diseases.

项目概要 2015 年联合国艾滋病规划署的报告估计，尽管缺乏证据，仍有超过 3500 万人感染了艾滋病毒。抗逆转录病毒药物疗法 (ART) 是一种绝育疗法，可有效抑制感染者的病毒复制。然而，只有 1700 万感染者能够获得 ART。需要每日给药的终生治疗，并且与一系列不需要的方面相关。广泛中和抗体（bNAb）可能能够补充或替代 ART。此类抗体已在人体临床试验中显示出前景，单剂量即可减少然而，HIV-1 感染者的病毒血症在治疗期间会迅速发生。 bNAb 浓度降低并选择腺相关病毒 (AAV)。载体可以在能够限制病毒进化的浓度下表达多年的 bNAb，并且然而，我们和其他团体已经出现了抗病毒药物。表达的 bNAb 的抗体 (ADA) 可以限制其表达在这个 K99/R00 提案中，我将解决与在功能性治疗中使用 AAV 递送的 bNAb 相关的三个关键问题。哪些 bNAb 具有与抑制 a 一致的生物物理和中和特性已确定感染？ 2) 载体和 AAV 衣壳优化能否增加 bNAb 表达并提供帮助限制宿主 ADA 反应？ 3) AAV 递送的 bNAb 能否抑制已确诊的 SHIV 感染？恒河猴，是否不需要 ART？通过回答这些问题，我们将确定如何最好使用 AAV 载体来治疗 AAV 感染，并为使用 AAV 的研究人员提供见解我对 AAV 和 HIV-1 系统的研究以及我对非人类的开发。作为 Ruth L. Kirschstein 研究员的灵长类项目为我提供了必要的培训 TSRI 为协作科学提供了出色的研究环境，特别是在艾滋病毒领域，我将参加 TSRI 和冷泉港提供的课程。我的导师 Farzan 博士将提供有关成为一名独立调查员的进一步培训。我的科学顾问委员会由 Ron Desrosiers、Susana Valente 和 Hyeryun 博士组成 Choe 致力于为我提供出色的培训，帮助我制定研究目标和提高我在未来 R01 提交中的资助写作技巧我在培训期间获得的技能。阶段将作为我自己在独立阶段的研究计划的基础，开发新的基因治疗载体并将这些载体应用于人类疾病的具体目标。