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Pharmacology and Experimental Neuroscience
Dolutegravir (DTG) is a first-line antiretroviral drug used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. Due to roll out of generic DTG-based regimen and rising pretreatment resistance to non-nucleoside reverse transcriptase inhibitors in resource limited countries, 15 million HIV-1 infected people will be treated with DTG by year 2025. This includes women of child-bearing age who remain a significant infected population. However, growing data have suggested that DTG is associated with birth defects. Thus, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained research interest. To this end, there is a knowledge gap of known adverse events reflecting DTG-associated trophoblasts impairments. We previously reported that DTG inhibits matrix metalloproteinases (MMPs) activities. It is known that activity of MMP-2 and MMP-9 are required for the successful invasion of trophoblasts during early pregnancy and abnormalities in the activities of these proteins can influence impairment in placental implantation, vascular restructuring, and fetal development. We now report that DTG reduces invasion abilities of trophoblasts. Herein, we evaluated concentration dependent effects of DTG on HTR-8 trophoblastic cells. DTG was found to inhibit activities of MMP-2 and 9 under normoxic and hypoxic conditions. Moreover, DTG treatment decreased expression of HIF-1α under both normoxic and hypoxic conditions. Interestingly, decrease in expression of beclin 1 protein was observed, suggesting an effect on autophagy. Further assessments to determine the effects of DTG on trophoblasts functions showed that DTG reduces migration and invasion abilities of HTR-8 cells. In addition, studies performed in pregnant mice validated that DTG decreases HIF-1α expression in placenta. Thus, our proof-of-concept work concludes that DTG can potentially impair placental development by affecting HIF-1α expression and MMPs activities.
Dolutegravir, HIV-1, Placenta, Matrix metalloproteinases, Hypoxia.
Speakar, Brianna; Foster, Emma; and Bade, Aditya N., "Dolutegravir reduces migration and invasion abilities of trophoblasts by decreasing HIF-1α expression and MMPs activities" (2022). Posters: 2022 Summer Undergraduate Research Program. 21.