AAV-mediated delivery of eCD4-Ig for prevention and treatment of perinatal HIV infection

AAV 介导的 eCD4-Ig 递送用于预防和治疗围产期 HIV 感染

基本信息

批准号：
10406312
负责人：
Mauricio de Aguiar Martins
金额：
$ 81.89万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-07 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406312
关键词：
2 year old AIDS/HIV problem Address Adherence Adult Animals Antibodies Binding Birth Blood Chemical Analysis Blood Circulation Breast Breastfed infant CCR5 gene CXCR4 gene Caring Cell Count Cells Child Childhood Chronic Phase Data Dependovirus Early treatment Foundations Gene Transfer HIV HIV Entry Inhibitors HIV Infections HIV-1 HIV-2 Healthcare Human Immune Immunity Immunoglobulin G Immunoglobulin Genes Immunoglobulins Immunologic Deficiency Syndromes Infant Infant Health Infection Infrastructure Ingestion Interphase Cell Intervention Kinetics Macaca mulatta Mediating Modeling Monitor Monkeys Morbidity - disease rate Mother-to-child HIV transmission Mothers Neonatal Newborn Infant Oral Pathogenicity Pharmaceutical Preparations Placebos Postpartum Period Prevention Primate Lentiviruses Property Prophylactic treatment Reporting Reproducibility Research Resource-limited setting SIV Safety Serum Skeletal Muscle Testing Time Transgenes Treatment-related toxicity Vaccines Vertical Disease Transmission Viremia Virus Virus Diseases Virus Replication Weight Gain adeno-associated viral vector antenatal antibody detection antiretroviral therapy base combat env Gene Products experience experimental study gene therapy immunogenicity immunological intervention in vivo infant infection inhibitor interest low income country mature animal mimetics mortality neonatal period neonate pediatric human immunodeficiency virus infection peptidomimetics perinatal HIV placebo group postnatal pre-clinical prenatal prevent programs prophylactic receptor simian human immunodeficiency virus therapy resistant transgene expression virtual

项目摘要

PROJECT SUMMARY Mother-to-child transmission of human immunodeficiency virus (HIV) still results in hundreds of thousands of new pediatric HIV infections every year, especially in resource-poor areas of the world where access to antenatal/postnatal antiretroviral therapy (ART) is limited. Sadly, in the absence of ART, >50% of HIV- infected infants die by 2 years of age. Since ART alone will not be sufficient to end the morbidity and mortality associated with HIV/AIDS in children, there is an urgent need for developing practical interventions to prevent and treat pediatric HIV infection. To that end, this project will evaluate the potential of gene therapy with the potent and extremely broad HIV inhibitor eCD4-Ig to prevent and treat perinatal HIV infection. eCD4-Ig is a chimeric molecule consisting of the outer domains of CD4, an IgG Fc portion, and a co-receptor mimetic peptide. eCD4-Ig has unmatched breadth and very potent effector activities against HIV-1, HIV-2, and SIV. The eCD4-Ig gene will be delivered to infant rhesus macaques (RMs) via adeno-associated virus (AAV)-mediated gene transfer. AAV vectors are safe and can transduce both dividing and non-dividing cells. Critically, AAV-driven transgene expression in long-lived cells, such as those of skeletal muscle, can last for years, possibly decades. While AAV-mediated delivery of eCD4-Ig has been shown to protect adult RMs against challenge with pathogenic immunodeficiency viruses bearing highly divergent Envelope proteins, this approach has never been tested in infants. We have recently partnered with the Farzan lab to characterize the kinetics of eCD4-Ig expression in infant RMs treated with AAV/eCD4-Ig at birth. Compared to adult animals, AAV/eCD4-Ig-treated newborn RMs experienced substantially higher levels of eCD4-Ig and lower levels of antibodies against the eCD4-Ig molecule. Note that these anti-drug antibodies (ADAs) are highly detrimental to AAV-mediated delivery of immunoglobulins because they can clear the molecules from circulation, thereby reducing the efficacy of this approach. The low levels of ADAs observed in the AAV/eCD4-Ig-treated infants is consistent with previous reports of neonates developing tolerance to AAV-delivered transgene products. Given the ability of AAV vectors to promote sustained transgene expression after a one-time administration, and the unique window of opportunity offered by the neonatal period to achieve robust AAV-driven expression of eCD4-Ig in vivo, we postulate that AAV-mediated delivery of eCD4-Ig to infants can prevent and treat postpartum HIV infection. In specific aim (SA) 1, we will characterize the safety profile of AAV/eCD4-Ig in infant RMs. In SA 2, we will determine if neonatal delivery of AAV/eCD4-Ig can prevent oral acquisition of SIVmac239 in RMs. In SA 3, we will assess if AAV-mediated delivery of eCD4-Ig to SIV-infected infant RMs can control viral replication without ART. If successful, the proposed experiments will build the pre-clinical foundation for testing AAV-mediated gene therapy with eCD4-Ig in infants as a means to prevent and treat perinatal HIV infection.

项目概要人类免疫缺陷病毒 (HIV) 的母婴传播仍导致数百人死亡每年有数以千计的新儿童艾滋病毒感染者，特别是在世界上资源匮乏的地区获得产前/产后抗逆转录病毒治疗（ART）的机会有限。可悲的是，在缺乏抗逆转录病毒治疗的情况下，>50% 的艾滋病毒- 受感染的婴儿在两岁时死亡。由于仅靠抗逆转录病毒疗法不足以消除发病率和死亡率与儿童艾滋病毒/艾滋病有关，迫切需要制定切实可行的干预措施来预防并治疗儿童艾滋病毒感染。为此，该项目将评估基因治疗的潜力有效且极其广泛的 HIV 抑制剂 eCD4-Ig，用于预防和治疗围产期 HIV 感染。 eCD4-Ig 是嵌合分子由 CD4 的外部结构域、IgG Fc 部分和共受体模拟肽组成。 eCD4-Ig 具有无与伦比的广度和针对 HIV-1、HIV-2 和 SIV 的非常有效的效应活性。 eCD4-Ig 基因将通过腺相关病毒（AAV）介导的基因传递给幼年恒河猴（RM）转移。 AAV 载体是安全的，可以转导分裂细胞和非分裂细胞。至关重要的是，AAV 驱动长寿细胞（例如骨骼肌细胞）中的转基因表达可以持续数年，甚至可能数十年。虽然 AAV 介导的 eCD4-Ig 递送已被证明可以保护成年 RM 免受致病性挑战免疫缺陷病毒携带高度不同的包膜蛋白，这种方法从未在婴儿。我们最近与 Farzan 实验室合作，表征了 eCD4-Ig 表达的动力学婴儿 RM 在出生时接受 AAV/eCD4-Ig 治疗。与成年动物相比，AAV/eCD4-Ig 治疗的新生 RM 经历了明显较高水平的 eCD4-Ig 和较低水平的针对 eCD4-Ig 分子的抗体。请注意，这些抗药物抗体 (ADA) 对 AAV 介导的免疫球蛋白递送非常不利因为它们可以清除循环中的分子，从而降低这种方法的功效。低在 AAV/eCD4-Ig 治疗的婴儿中观察到的 ADA 水平与之前的新生儿报告一致对 AAV 传递的转基因产品产生耐受性。鉴于 AAV 载体能够促进持续的一次性给药后转基因表达，以及由为了在新生儿期实现体内 AAV 驱动的 eCD4-Ig 的强表达，我们假设 AAV 介导的向婴儿输送 eCD4-Ig 可以预防和治疗产后 HIV 感染。在具体目标 (SA) 1 中，我们将描述 AAV/eCD4-Ig 在婴儿 RM 中的安全性特征。在 SA 2 中，我们将确定新生儿是否分娩 AAV/eCD4-Ig 可以防止 RM 口服 SIVmac239。在 SA 3 中，我们将评估 AAV 是否介导向感染 SIV 的婴儿 RM 输送 eCD4-Ig 无需 ART 即可控制病毒复制。如果成功的话，拟议的实验将为测试 AAV 介导的 eCD4-Ig 基因治疗奠定临床前基础作为预防和治疗围产期艾滋病毒感染的一种手段。