eCD4-Ig for preventing and treating obstetric HIV infection

项目摘要 在全世界，妇女受艾滋病毒/艾滋病的影响仍然不成比例，特别是在非洲， 在撒哈拉非洲，近80%的青少年艾滋病毒新感染者是女性。由于高 尽管本区域的生育率很低，但妇女在其生育年中的很大一部分时间要么是怀孕，要么是怀孕。 母乳喂养。这是有意义的，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妊娠状态相比。事实上， 怀孕或最近分娩的妇女的发病率（即，在撒哈拉以南非洲 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。鉴于最近女性抗逆转录病毒治疗耐药艾滋病毒变种激增，以及事实上 一些抗逆转录病毒药物不能在怀孕期间安全使用，这是对抗产科艾滋病毒感染的新方法 是迫切需要的。在这里，我们将探讨安全性和抗病毒特性的抗体样艾滋病毒入境 eCD 4-IG抑制剂。因为eCD 4-IG模拟受体（CD 4） 和灵长类慢病毒的共受体（CCR 5和CXCR 4），它与几乎所有HIV或 猴免疫缺陷病毒（SIV）Env蛋白。因此，eCD 4-IG比任何单一的HIV特异性免疫球蛋白都要广泛。 迄今为止描述的广泛中和的单克隆抗体。鉴于这些令人印象深刻的性质，我们假设 eCD 4-IG可以预防和控制产科艾滋病毒感染。为了解决这一假设，我们将解决四个关键问题。 妊娠和产后雌性恒河猴中eCD 4-IG的安全性和抗病毒特性相关问题 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 eCD 4-IG在妊娠RM中的药代动力学？2)被动递送eCD 4-IG能阻断阴道SIV的获得吗 在怀孕的RM？3)被动递送eCD 4-IG能否抑制SIV感染的妊娠RM的病毒血症？4)可以 腺相关病毒表达的eCD 4-IG阻断产后RM患者经阴道获得SIVmac 239？总之， 这里提出的临床前实验将帮助我们评估eCD 4 - 1的预防和治疗潜力。 IG用于对抗产科HIV感染。重要的是，由于母体病毒血症是母体感染的一个强有力的预测因子， 儿童传播艾滋病毒，该项目的成功成果也可能有助于降低高发病率， 围产期艾滋病毒感染仍然困扰着资源贫乏地区。

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.