Bictegravir decreases expression of system L-amino acid transporters and inhibits leucine uptake activity in a human placental cell line

Abstract

Antiretroviral therapy (ART) improves maternal health and reduces perinatal HIV transmission; however, it has been associated with increased risk for adverse outcomes via mechanisms that are poorly understood. Branched-chain amino acids (BCAAs) are important for fetal development and cardiometabolic health. Alterations in BCAAs have been reported in pregnant people with HIV and children exposed to ART in utero. System L-amino acid transporters are key in transporting BCAAs across the placenta, but their functionality in the context of ART use has not been investigated. Here we examine the effects of antiretrovirals on the expression and function of system L transporters. Syncytialized BeWo cells were treated with atazanavir, darunavir, efavirenz, dolutegravir, raltegravir, bictegravir or cabotegravir for 24 h at C_max and half C_max therapeutic concentrations. Cytoplasmic and membrane protein expression of system L isoforms were quantified by western blot. System L transport activity was measured using [³H]-tritium-labelled L-leucine uptake assays in the presence or absence of a system L-specific inhibitor. System L isoforms LAT-1 and LAT-2 were primarily expressed in the plasma membrane, whereas LAT-4 expression was predominantly cytoplasmic. Bictegravir significantly reduced the protein levels of all 3 isoforms. Cabotegravir was associated with lower LAT-1 and LAT-4 and efavirenz with lower LAT-1 and LAT-2 levels. A reduction in leucine transport was only observed with bictegravir treatment. Bictegravir, which has been recently added to perinatal treatment guidelines, was associated with downregulation of system L expression and function in BeWo cells. Further in vivo studies are warranted to confirm our findings.