Project Summary Weight gain with Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), has been observed in People living with HIV (PLHIV) including postpartum women. How DTG-based ART regimens affect postpartum weight is not known. Understanding the impact of maternal DTG-regimens on the physiology of postpartum body weight regulation has clinical significance as postpartum weight retention is known to increase future maternal risk of overweight, obesity and non-communicable diseases (NCD). DTG-based ART is being rolled as the first line regimen in Sub-Saharan Africa for HIV management. Therefore, it is imperative to better understand how DTG regimens affect the physiology of postpartum body weight regulation and appetite, to identify potential interventions to reduce future overweight and NCD risk in this population. To address this research gap, we propose to leverage our R01 study (MI-DART), focused on energy intake and energy expenditure in a cohort of mother-infant dyads with and without HIV, to further study the impact of DTG on appetite regulation in these postpartum women (Aim 1). This maternal–infant cohort will also allow us to define the impact of maternal DTG-ART regimen on appetite in their HIV exposed uninfected (HEU) infant compared to HIV unexposed uninfected infants (Aim 2), and how they relate to infant growth and body composition. In addition to the comparison by maternal ART regimen, our study will help us understand the mechanisms behind one of the most clinically significant observations in HEU infants: infant growth deficits in HEU infants with mothers on non-DTG regimen compared to HUU infant; and whether maternal DTG containing ART regimens have a similar impact. We will use targeted approaches to assess appetite regulation, including subjective appetite questionnaires and pre- and post-prandial levels of objective panels of appetite-stimulating and appetite-reducing peptides and hormones, along with short-chain fatty acids that regulate levels of these hormones. Unbiased approaches include assessment of the microbiome as it regulates these hormones and short-chain fatty acids involved in appetite. We will pair these measures with secondary objective assessments of physical activity along with energy intake and total energy expenditure data obtained from the parent study to better understand the impact of appetite, energy intake and energy expenditure. Through these two aims, we address an urgent need to understand how maternal DTG impacts the physiology of body weight regulation and appetite in postpartum women and their HEU infants. These maternal- infant populations have a unique physiological profile with increased energy demands on the lactating mother and breastfeeding infant to sustain growth. Our detailed metabolic assessments will further help identify potential therapeutics (e.g. related to intake/appetite, expenditure, or metabolic pathways) for management of postpartum weight and infant grow...