eCD4-Ig for preventing and treating obstetric HIV infection

项目总结 在世界范围内，妇女继续受到艾滋病毒/艾滋病的不成比例的影响，但在亚 撒哈拉非洲，在那里，青少年中近80%的新艾滋病毒感染是女性。因为有这么高 在该地区的生育率方面，妇女在其生育期中的很大一部分时间要么怀孕，要么 母乳喂养。这是相关的，因为非洲妇女感染艾滋病毒的风险增加了4倍 在妊娠和产后阶段与非怀孕状态进行比较。事实上，汇集在一起的艾滋病毒 撒哈拉以南地区怀孕或新近分娩(即产后)妇女的发病率 非洲超过了“高危人群”，如女性性工作者。此外，由于怀孕和 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- 艾滋病治疗。鉴于最近女性中抗逆转录病毒治疗耐药艾滋病毒变种的激增，以及 一些抗逆转录病毒药物在怀孕期间不能安全使用，这是抗击产科艾滋病毒感染的新方法 都是迫切需要的。在这里，我们将探索抗体样HIV进入的安全性和抗病毒特性 在孕期和产后期抑制eCD4-Ig。因为eCD4-Ig模拟的是受体(CD4) 和灵长类慢病毒的辅助受体(CCR5和CXCR4)，它能与几乎任何HIV或 猴免疫缺陷病毒(SIV)包膜蛋白。因此，eCD4-Ig比任何单一的HIV特异性免疫球蛋白都要广泛 到目前为止所描述的广泛中和的单抗。鉴于这些令人印象深刻的特性，我们假设 说明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 孕产期雌性恒河猴使用eCD-4-Ig的安全性和抗病毒特性的相关问题 猕猴(RMS)。1)新生儿Fc受体亲和力增强突变如何影响其生物分布和 ECD_4-Ig在妊娠RMS中的药代动力学？2)被动注射eCD_4-Ig能否阻断阴道SIV感染 在妊娠RMS？3)被动注射eCD-Ig能抑制SIV感染的孕妇RMS的病毒血症吗？4)可以 腺相关病毒表达的eCD4-Ig阻断产后RMS患者SIVmac239的阴道感染？总而言之， 这里提出的临床前实验将帮助我们评估eCD4-1的预防和治疗潜力。 免疫球蛋白用于抗击产科艾滋病毒感染。重要的是，因为母亲的病毒血症是母婴传播的强烈预测因素。 在儿童传播艾滋病毒方面，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。 仍然困扰资源匮乏地区的围产期艾滋病毒感染。

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.