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

• 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
• 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

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.

项目摘要 艾滋病毒的母婴传播仍然导致数百人死亡， 每年有数千名新的儿童艾滋病毒感染，特别是在世界上资源贫乏的地区， 获得产前/产后抗逆转录病毒疗法的机会有限。不幸的是，在没有抗逆转录病毒疗法的情况下，>50%的艾滋病毒- 受感染的婴儿在2岁前死亡。由于单靠抗逆转录病毒疗法不足以消除艾滋病的发病率和死亡率， 与儿童艾滋病毒/艾滋病相关，迫切需要制定切实可行的干预措施来预防 治疗儿童艾滋病感染。为此，该项目将评估基因治疗的潜力， 有效且极广泛的HIV抑制剂eCD 4-IG，用于预防和治疗围产期HIV感染。eCD 4-IG是一种 由CD 4的外部结构域、IgG Fc部分和共受体模拟肽组成的嵌合分子。 eCD 4-IG具有无与伦比的抗HIV-1、HIV-2和SIV的广度和非常有效的效应子活性。eCD 4-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，并且可以使分裂细胞和非分裂细胞均增殖。关键是， 转基因在长寿细胞如骨骼肌细胞中的表达可持续数年，可能数十年。 虽然AAV介导的eCD 4-IG递送已显示保护成年RM免受病原性免疫球蛋白的攻击，但其对免疫球蛋白的抑制作用并不显著。 尽管免疫缺陷病毒携带高度不同的包膜蛋白，但这种方法从未在 婴儿。最近，我们与Farzan实验室合作，研究eCD 4-IG表达的动力学特征。 出生时用AAV/eCD 4-IG治疗的婴儿RM。与成年动物相比，AAV/eCD 4-Ig处理的新生RM 经历了显著更高水平的eCD 4-IG和更低水平的针对eCD 4-IG分子的抗体。 注意，这些抗药物抗体（ADA）对AAV介导的免疫球蛋白递送是高度有害的。 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/eCD 4-Ig治疗的婴儿中观察到的ADA水平与先前的新生儿报告一致。 发展对AAV递送的转基因产物的耐受性。考虑到AAV载体促进持续免疫的能力， 在一次性施用后的转基因表达，以及由转基因技术提供的独特的机会窗口。 为了在体内实现eCD 4-IG的稳健的AAV驱动的表达，我们假设AAV介导的eCD 4-Ig在新生儿期是稳定的。 向婴儿递送eCD 4-IG可预防和治疗产后HIV感染。在具体目标（SA）1中，我们将 表征AAV/eCD 4-IG在婴儿RM中的安全性特征。在SA 2中，我们将确定新生儿分娩是否 AAV/eCD 4-IG可预防RM中SIVmac 239的口服获得。在SA 3中，我们将评估AAV介导的 向SIV感染的婴儿RM递送eCD 4-IG可以在不使用ART的情况下控制病毒复制。 所提出的实验将为测试AAV介导的eCD 4-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。