Abstract
Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme’s catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.
Highlights
The World Health Organization updated guidance recommends continuation or initiation of antiretroviral therapy (ART) in all pregnant and breastfeeding women living with human immunodeficiency virus type-1 (HIV-1) infection [1]
To determine the proteolytic activity of matrix metalloproteinases (MMPs) 2 and 9, equal amount of protein (3 μg) from cell culture medium was loaded on SDS-PAGE containing gelatin
For the first time, we show that DTG inhibits MMPs activities in fetal brain during gestation and as such impairs neurodevelopment
Summary
The World Health Organization updated guidance recommends continuation or initiation of antiretroviral therapy (ART) in all pregnant and breastfeeding women living with human immunodeficiency virus type-1 (HIV-1) infection [1]. With increased numbers of infected pregnant women receiving ART, over a million HIV-1-exposed but uninfected (HEU) children are born each year [2, 3]. This results in potential exposures of fetuses to antiretroviral drugs (ARVs) during development. Emerging data demonstrates that HEU children have inferior health outcomes compared to their HIV-1-unexposed counterparts [4]. This highlights an immediate need to identify any ARV or class thereof associated with adverse pregnancy outcomes. There is a need to define any altered prenatal and postnatal developmental outcomes after ARV exposures and elucidate underlying mechanisms
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call