eCD4-Ig for preventing and treating obstetric HIV infection

eCD4-Ig 用于预防和治疗产科 HIV 感染

基本信息

批准号：
10415989
负责人：
Mauricio de Aguiar Martins
金额：
$ 79.5万
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：
2020-08-13 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415989
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 Behavioral Binding Biodistribution Biological Biological Factors Biological Products 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 Resource-limited setting 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 virtual young woman

项目摘要

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.

项目概要世界范围内，妇女仍然不成比例地受到艾滋病毒/艾滋病的影响，特别是在亚健康地区。撒哈拉非洲地区，青少年中近 80% 的新艾滋病毒感染者是女性，因为感染率很高。就该地区的生育率而言，妇女在其生育年龄中的很大一部分时间是在怀孕或这很重要，因为非洲妇女感染艾滋病毒的风险增加了 4 倍。与非怀孕状态相比，妊娠期和产后阶段确实存在艾滋病毒合并情况。撒哈拉以南地区怀孕或最近分娩（即产褥期）妇女的发病率非洲超过了“高风险人群，例如女性性工作者”。哺乳期妇女继续被排除在临床研究之外，她们不太可能从最新的抗- 鉴于最近女性中抗逆转录病毒疗法耐药的艾滋病病毒变异体数量激增，而且事实上一些抗逆转录病毒药物在怀孕期间不能安全使用，这是对抗产科艾滋病毒感染的新方法在这里，我们将探讨类似抗体的 HIV 入口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)。和灵长类慢病毒的辅助受体（CCR5 和 CXCR4），它强烈结合并中和几乎任何 HIV 或因此，eCD4-Ig 比任何单一的 HIV 特异性都更广泛。鉴于迄今为止所描述的广泛中和单克隆抗体，我们假设具有这些令人印象深刻的特性。 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问题。与怀孕和产褥雌性恒河猴中 eCD4-Ig 的安全性和抗病毒特性相关的问题猕猴 (RM) 1) 新生儿 Fc 受体亲和力增强突变如何影响生物分布和妊娠 RM 中 eCD4-Ig 的药代动力学 2) eCD4-Ig 被动递送能否阻止阴道 SIV 获得 3) 被动分娩 eCD4-Ig 能否抑制感染 SIV 的妊娠 RM 的病毒血症？腺相关病毒表达的 eCD4-Ig 会阻止产后 RM 的阴道获得 SIVmac239 总而言之，这里提出的临床前实验将帮助我们评估 eCD4- 的预防和治疗潜力免疫球蛋白用于对抗产科艾滋病毒感染，重要的是，因为母体病毒血症是母婴感染的有力预测因素。儿童艾滋病毒传播，该项目的成功成果也可能有助于降低艾滋病毒的高发病率围产期艾滋病毒感染仍然困扰着资源匮乏的地区。