Cocaine and cannabinoids antagonize art efficacy that promotes HIV infection and inflammatory responses at the maternal-fetal interface

The National Institute on Drug Abuse awarded Emory University $2,050,038 on May 15, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to investigate how cocaine and cannabis use antagonize antiretroviral therapy efficacy and promote HIV infection and inflammatory responses at the maternal-fetal interface.

The research addresses the knowledge gap regarding comorbid substance use and HIV/antiretroviral therapy impacts on placental function in pregnant women living with HIV. The study evaluates pharmacologic mechanisms by which cocaine and cannabis polysubstance use alter antiretroviral therapy placental transport and metabolism through PXR signaling, immunologic and virologic mechanisms underlying effects of comorbid substance use and HIV/antiretroviral therapy on the placenta, and whether HIV, antiretroviral therapy, and comorbid substance use are associated with placental dysfunction and inflammation in both HIV-positive and HIV-negative pregnancies.

Performance of work occurs in Atlanta, Georgia. The project period extends through February 28, 2031.

Abstract

Despite the effectiveness of antiretroviral therapies (art) in reducing vertical transmission, maternal HIV infection and art exposure during pregnancy is associated with immune dysregulation in mothers, along with inflammation and significant pathology in the placenta. Compounding these risks is the increasing prevalence of substance abuse among pregnant women and people living with HIV. Compared with the general population, HIV-positive women had higher use of marijuana (15% VS 7%) and cocaine/crack (17% VS 0.1%), and recent findings suggest that 6-18.3% of pregnant women report using illicit drugs throughout gestation. Despite this increase, little is known about the impact of comorbid substance use and HIV/art on the placenta. In this study we seek to fill this critical knowledge GAP by elucidating the mechanisms driving placental dysfunction in pregnant women living with HIV with comorbid substance use and examine how cocaine and/or cannabis use may exacerbate viral infectivity, inflammation, and art efficacy at the maternal- fetal interface. We hypothesize cocaine and cannabis polysubstance use antagonize placental art transport and metabolism through PXR signaling, which promotes HIV replication, inflammatory responses, and placental abnormalities associated with adverse maternal and fetal outcomes. We will address this by evaluating: pharmacologic mechanisms by which comorbid substance use and HIV alter art placental efficacy (aim 1), immunologic and virologic mechanisms underlying effects of comorbid substance use and HIV/art on the placenta (aim 2), and evaluate whether HIV, art and/or comorbid substance use is associated with dysfunction and inflammation in placentae and maternal blood from HIV (+) and (-) pregnancies (aim 3).