# Exposure to Frontline Antiretroviral Dolutegravir Disrupts Oligodendrocyte Development Across Differentiation Stages

## TL;DR

This study shows that the HIV drug dolutegravir disrupts the development of brain cells that produce myelin, which is crucial for proper nervous system function in newborns.

## Contribution

The study identifies dolutegravir as the specific drug in a common ART cocktail that inhibits oligodendrocyte maturation, independent of the integrated stress response.

## Key findings

- Dolutegravir, but not other drugs in Triumeq, inhibits oligodendrocyte maturation and myelin production in a concentration-dependent manner.
- DTG exposure causes transcriptional changes linked to stress pathways, amino acid starvation, and mitochondrial dysfunction.
- DTG's inhibition of OL maturation occurs regardless of exposure timing and is largely independent of the integrated stress response.

## Abstract

The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we have limited knowledge of how ART drugs that cross the placental barrier affect fetal development, particularly in the central nervous system (CNS). During gestation, large populations of oligodendroglia are produced that are responsible for critical postnatal CNS myelination enabling appropriate neurological function. Previous studies have shown that antiretrovirals impair oligodendrocyte (OL) differentiation leading us to hypothesize that OL maturation might be inhibited by exposure to a frontline ART drug cocktail (Triumeq®) prescribed during pregnancy containing dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC). In this study, we demonstrated that exposing primary rat oligodendrocyte precursor cells (OPCs) and OLs to the Triumeq drug combination decreased OL maturation and myelin protein production in a concentration-dependent manner, and that DTG was solely responsible. Regardless of the timing of exposure during OL development, a high concentration of DTG inhibited OL maturation. Bulk RNA sequencing revealed transcriptional changes after DTG exposure related to a variety of cellular mechanisms, including cellular responses to stress pathways, amino acid starvation, and mitochondrial dysfunction. Although we found that DTG robustly activated the integrated stress response (ISR), attempted rescue experiments showed that DTG primarily inhibits OL maturation independently of the ISR. Collectively, our novel data on DTG underscore the necessity of investigating how ART drugs that are administered during pregnancy and cross the placental barrier can affect fetal CNS development.