Impact of Chronic Prenatal THC Exposure on SIV-associated Inflammation and Impairments in Placental and Fetal Development - PROJECT SUMMARY/ABSTRACT HIV remains a major public health concern, particularly among pregnant individuals. Even with suppressive antiretroviral therapy (ART), pregnant people with HIV (PWH) have significantly greater risk of maternal mortality and adverse pregnancy outcomes as compared to pregnant people without HIV. This risk has been linked with placental inflammation and vascular malperfusion, which can lead to placental dysfunction and cause adverse fetal development. Additionally, in utero exposure to maternal inflammation, a hallmark of HIV infection that persists despite ART, contributes to poor fetal and infant immunity and influences short- and long-term offspring health. Thus, defining the underlying pathways and effects of maternal and placental inflammation and placental dysfunction to inform development of therapies to mitigate adverse pregnancy outcomes in PWH is crucial. Cannabis is the most commonly used federally illicit substance among pregnant PWH and, independent of concurrent HIV infection, is associated with increased pregnancy complications (e.g., preterm birth, stillbirth) and negative impacts on offspring health and development. Although the current literature suggests a likely additive adverse effect of cannabis use on pregnancy and fetal outcomes among PWH, there is insufficient evidence to validate this theory. This gap in knowledge is due in part to 1) the practical and ethical constraints of conducting in vivo or ex vivo studies among pregnant PWH to examine the biological mechanisms by which THC impacts pregnancy outcomes; 2) the inability to serially sample critical tissue sites (e.g., lymph nodes, amniotic fluid) in pregnant PWH; and 3) the paucity of relevant preclinical models that have strong translation to human health. Our central hypothesis is that chronic prenatal THC exposure in ART-treated SIV-infected rhesus macaques will result in disruptions in viral control, have an additive negative impact on placental insufficiency and vascular dysregulation, and result in adverse fetal development that are all primarily mediated by immune dysfunction. To test this hypothesis, we will leverage our translational, first-in-kind rhesus macaque model of chronic (i.e., daily) edible THC use and ART-treated SIV infection, longitudinal biological sampling and advanced in vivo imaging. Our comprehensive assessments at the maternal, placental, and fetal levels and in-depth data analysis strategy will provide much needed information of the impact of THC during ART-treated SIV infection on maternal SIV- associated immunopathology and viral dynamics (Aim 1), placental development and function (Aim 2), and fetal development (Aim 3) that would be impossible to study in humans. This study will also generate a unique, comprehensive rhesus macaque tissue bank of biological samples available to all researchers for future studies. With the continued and concerning rise in prenatal cannabis use by PWH, this is a necessary and impactful first step to generate critically needed information on the effects of combined THC exposure, ART treatment, and SIV infection on maternal, placental, and fetal outcomes to guide healthcare providers on pregnancy management to improve future maternal and offspring health.
