eCD4-Ig for preventing and treating obstetric HIV infection

eCD4-Ig 用于预防和治疗产科 HIV 感染

• 批准号: 10238165
• 负责人: Mauricio de Aguiar Martins
• 金额: $ 19.8万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238165
• 关键词: AIDS/HIV problem; Address; Adolescent; Affect; Affinity; Africa South of the Sahara; African; Age; Amniotic Fluid; Anti-HIV Therapy; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Behavioral; Binding; Biodistribution; Biological; Biological Factors; Birth; Breast Feeding; CCR5 gene; CXCR4 gene; Clinical; Clinical Research; Dependovirus; Discipline of obstetrics; Dose; Drug Kinetics; Fc Receptor; Female; Fertility Rates; Foundations; Gene Transfer; HIV; HIV Entry Inhibitors; HIV Infections; HIV resistance; HIV therapy; Health Personnel; Home; Immunity; Immunoglobulin G; Incidence; Individual; Infection; Infusion procedures; Intervention; Lactation; Late pregnancy; Learning; Macaca mulatta; Measures; Mediating; Modification; Monitor; Morbidity - disease rate; Mother-to-child HIV transmission; Mothers; Mucous Membrane; Mutation; Outcome; Passive Immunization; Persons; Pharmaceutical Preparations; Placenta; Plague; Postpartum Period; Pregnancy; Pregnant Women; Primate Lentiviruses; Property; Prophylactic treatment; Resources; Risk; SIV; Safety; Serum; Sum; Testing; Therapeutic; Third Pregnancy Trimester; Time; Vagina; Variant; Viremia; Virus; Virus Replication; Woman; antiretroviral therapy; base; combat; cost; env Gene Products; experimental study; female sex worker; fetal; fitness; high risk; improved; male; maternal serum; mimetics; mortality; neonatal Fc receptor; neutralizing monoclonal antibodies; perinatal HIV; pre-clinical; pregnant; prevent; prophylactic; receptor; reproductive; sex; simian human immunodeficiency virus; social culture; virology; virtual; young woman

PROJECT SUMMARY Women continue to be disproportionately affected by HIV/AIDS worldwide, but particularly in sub- Saharan Africa, where nearly 80% of new HIV infections among adolescents are in females. Because of the high fertility rates in the region, women spend a significant fraction of their reproductive years either pregnant or breastfeeding. This is relevant because the risk of HIV acquisition among African women increases up to 4-fold during the gestational and postpartum stages compared to the non-pregnant state. Indeed, the pooled HIV incidence rates among women who are pregnant or have recently given birth (i.e., puerperal) in sub-Saharan Africa exceed those for “high risk individuals, such as female sex workers. Additionally, because pregnant and lactating women continue to be excluded from clinical research, they are unlikely to benefit from the latest anti- HIV therapies. Given the recent spike in antiretroviral therapy-resistant HIV variants in women and the fact that some antiretrovirals cannot be safely used during pregnancy, new ways for combating obstetric HIV infection are urgently needed. Here we will explore the safety and antiviral properties of the antibody-like HIV entry inhibitor eCD4-Ig during pregnancy and the postpartum period. Because eCD4-Ig emulates the receptor (CD4) and coreceptors (CCR5 & CXCR4) of primate lentiviruses, it binds avidly to and neutralizes virtually any HIV or simian immunodeficiency virus (SIV) Env proteins. As a result, eCD4-Ig is broader than any single HIV-specific broadly neutralizing monoclonal antibody described to date. Given these impressive properties, we postulate that eCD4-Ig can prevent and control obstetric HIV infection. To address this hypothesis, we will tackle four key questions related to the safety and antiviral properties of eCD4-Ig in pregnant and puerperal female rhesus macaques (RMs). 1) How do neonatal Fc receptor affinity-enhancing mutations affect the biodistribution and pharmacokinetics of eCD4-Ig in pregnant RMs? 2) Can passive delivery of eCD4-Ig block vaginal SIV acquisition in pregnant RMs? 3) Can passive delivery of eCD4-Ig suppress viremia in SIV-infected pregnant RMs? 4) Can adeno-associated virus-expressed eCD4-Ig block vaginal acquisition of SIVmac239 in puerperal RMs? In sum, the pre-clinical experiments proposed here will help us gauge the prophylactic and therapeutic potential of eCD4- Ig for combatting obstetric HIV infection. Importantly, since maternal viremia is a strong predictor of mother-to- child transmission of HIV, a successful outcome in this project may also contribute to reducing the high rates of perinatal HIV infection that still plague resource-poor regions.

项目摘要 妇女在全球范围内受到艾滋病毒/艾滋病的影响不成比例，尤其是在 撒哈拉非洲，在青少年中，几乎80％的新艾滋病毒感染是女性。因为很高 该地区的生育率，妇女在怀孕或复制年中花费很大一部分 哺乳。这很重要，因为非洲妇女中艾滋病毒收购的风险高达4倍 与非妊娠状态相比，妊娠和产后阶段。确实，汇总的艾滋病毒 萨哈拉以下孕妇或最近出生的妇女的发病率（即Puerperal） 非洲超过“高风险个人，例如女性性工作者。此外，由于怀孕和 哺乳期继续被排除在临床研究之外的妇女，她们不太可能受益于最新的反 - 艾滋病毒疗法。鉴于最近在女性抗逆转录病毒疗法抗性艾滋病毒变种中的峰值以及 某些抗逆转录病毒在怀孕期间无法安全使用，这是打击产科HIV感染的新方法 迫切需要。在这里，我们将探索类似抗体的HIV进入的安全性和抗病毒特性 怀孕期间和产后期间的抑制剂ECD4-Ig。因为ECD4-ig模拟受体（CD4） 灵长类动病毒的crocectors（CCR5＆CXCR4），它与几乎任何艾滋病毒或 猿猴免疫缺陷病毒（SIV）ENV蛋白。结果，ECD4-Ig比任何单一的HIV特异性 迄今为止描述的广泛中和单克隆抗体。鉴于这些令人印象深刻的特性，我们假设 ECD4-IG可以预防和控制产科HIV感染。为了解决这一假设，我们将解决四个关键 与ECD4-Ig在怀孕和卑鄙的雌性恒河主中的安全性和抗病毒特性有关的问题 猕猴（RMS）。 1）新生儿FC受体亲和力增强突变如何影响生物分布和 孕妇RMS中ECD4-Ig的药代动力学？ 2）可以被动地传递ECD4-IG Block阴道SIV获取 在怀孕的RMS中？ 3）可以被动递送ECD4-Ig抑制SIV感染的孕妇RMS中的病毒血症吗？ 4）可以被动递送ECD4-Ig抑制SIV感染的孕妇RMS中的病毒血症吗？ 腺相关病毒表达的ECD4-IG阻滞sivmac239在Puerperal RMS中的阴道习得？总而 这里提出的临床前实验将有助于我们衡量ECD4-的预防和治疗潜力 IG打击产科艾滋病毒感染。重要的是，由于孕产妇病毒血症是母亲到母亲的有力预测指标 艾滋病毒的儿童传播，该项目的成功结果也可能有助于降低高率 围产期艾滋病毒感染仍然困扰着资源贫乏的地区。