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.