There is increasing evidence that HIV exposed uninfected (HEU) infants are at risk for adverse metabolic, infectious, and neurodevelopmental outcomes when compared to HIV unexposed uninfected (HUU) infants. HEU infants show patterns and severity of infections typical of an underlying immune deficiency, persisting over the first few years of life, even among HEU infants not exposed to ART. Maternal immune responses to infections during pregnancy is implicated in the intrauterine adaptive immune responses of their unaffected neonates. The relationship between the immune systems of HIV-infected pregnant women and their HEU infants has been largely unexplored. The central premise of the proposed studies is that maternal immunity modulates early immune responses in their HEU newborns. Using a systems biology approach, we will examine pro-inflammatory and immune pathways within the transcriptome of peripheral blood mononuclear cells and plasma biomarkers from pregnant HIV-infected women and their infants enrolled in PACTG 316. Results will be compared to HIV- uninfected healthy pregnant women and HUU infants utilizing plasma, cryopreserved cells, and data from IMPAACT biorepositories and leveraged against completed clinical studies of HUU infants and healthy uninfected pregnant women. The primary goal of the study is to determine how perturbations by HIV and pregnancy alters maternal immune pathways and influences the early immune and inflammatory profiles in their babies. There are two specific aims: Aim 1. To identify inflammatory immune pathways and genes perturbed by pregnancy and HIV infection in women receiving ART and determine if these pathways are perturbed in their infants. Aim 2. To compare plasma biomarker and gene profiles associated with pro- and anti-inflammatory pathways in pregnant women with HIV and their HEU infants to profiles in uninfected pregnant women and their HUU infants, at birth and at 6 months of age. The study approach will define the global transcriptome of HIV-infected pregnant women with incomplete and complete viral suppression and their HEU infants receiving ART to determine how maternal immune ecology shapes human immune development. The project incorporates a multi-dimensional assessment of intracellular signaling pathways by combining next generation sequencing (NGS) with multiplex analysis of plasma biomarkers profiles to provide a clear portrait of how HEU and HUU newborns differ. More importantly, the results are likely to transcend HIV pathogenesis and be applicable to multiple maternal inflammatory conditions that affect the fetus and newborn.