Abstract Despite the rapid scale-up of lifelong triple antiretroviral therapy (ART) among pregnant women living with HIV (WLH), children born to WLH continue to have an increased risk of low birth weight (LBW), morbidity, and mortality compared to infants born to women who are not living with HIV. Although the association between LBW and decreased child survival has been well studied, the biological mechanisms linking HIV or ART and LBW are not well described. To better understand how HIV/ART increases the risk of LBW, we leverage an ongoing, well-characterized cohort of women living with HIV enrolled in a trial of data-driven continuous quality intervention to improve long term outcomes of ART in Kinshasa, Democratic Republic of Congo; our specific focus is on HIV-associated inflammation, immune activation, and microbial communities in the context of universal ART. A cohort of 600 women living with HIV on ART and 600 HIV-negative control along with their HIV-exposed un-infected (HEU) and HIV unexposed (HU) infants will be recruited and followed up through delivery and up to 12 months postpartum to determine how HIV/ART-induced placental dysfunction (Aim 1) or microbial dysbiosis (Aim 2) modulate the risk of LBW and subsequent infant mortality. Using biological specimen obtained from those women, we will document histopathologic placental abnormalities (e.g. necrosis) and measure levels of markers of inflammation, immune activation, and microbial translocation. We will also use a cutting-edge microbiome and virome toolkit with machine learning and ecosystem modeling approaches to evaluate associations between these entities and inflammation and LBW, as well as in silico test myriad mechanistic hypotheses derived from functional analyses. We expect that completion of these complementary aims will provide insight into the biological mechanism(s) associated with increased risk of LBW among HIV-exposed infants. This insight could ultimately identify an optimal HIV- treatment or care modality for pregnant WLH: one which promotes maternal health, prevents HIV mother-to-child transmission, and maximizes infant survival.