ADolutegravir (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 (NNRTIs) in resource limited countries (RLCs), 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 and postnatal developmental neurologic abnormalities following periconceptional usage and thus, concerns have emerged for its usage in pregnant women or those of child-bearing age. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal neurodevelopmental outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG was found to be a broad-spectrum MMPs inhibitor. It was more potent MMPs inhibitor than doxycycline. DTG was found to bind Zn++ at the catalytic domain to inhibit MMPs activities. Moreover, inhibition of MMPs activity was found to be an integrase strand transfer inhibitor (INSTI) class effect. Studies performed in pregnant mice showed that DTG readily reaches to the fetal central nervous system (CNS) during gestation and inhibits MMPs activity during critical period of brain development. Further postnatal evaluation of brain health in mice pups identified neuroinflammation and neuronal damage following in utero DTG exposure. Thus, we conclude that DTG inhibition of MMPs activities during gestation has the potential to affect pre- and post-natal neurodevelopment.

Summary: With an increased coverage of antiretroviral therapy (ART) for pregnant and breastfeeding women worldwide, >1 million HIV-exposed uninfected (HEU) children are born every year. With recommended wide-spread use of DTG-based regimen worldwide during pregnancy and increased concerns about DTG-associated neurodevelopmental abnormalities, there is an urgent need to identify unknown adverse drug effects on CNS development and underlying mechanism. Prior works focused on determining relationships between folate levels or transport pathways and DTG-associated birth defects failed to conclusively generate any cause-effect relationships. To this end, we show, for the first time, that DTG inhibits activity of matrix metalloproteinases (MMPs) during critical period of fetal CNS development, which could affect postnatal neurologic outcomes.

Main Target Audience: Anyone studying neural development, neuroscience, metalloproteinases (MMPs), pharmacology, immunology, inflammation, or human immunodeficiency virus type 1 (HIV-1). Also has relevance to clinicians.

Why should you attend?: In this webinar, Dr. Bade will discuss a potential link between neurodevelopmental abnormalities and antiviral dolutegravir treatment in pregnant women. You will learn how a mechanism of metalloproteinase inhibition in the prenatal brain of mice may explain these abnormalities.

Presented by: Aditya N. Bade, PhD
Instructor
University of Nebraska Medical Center; Department of Pharmacology and Experimental Neuroscience

Topic: Neuroscience

Gut dysbiosis is increasingly associated with the pathogenesis of protein conformational diseases such as Parkinson’s and ALS. Therefore, understanding the microbial contribution to protein stability and disease is critical for developing more effective interventions. The Czyz lab employs C. elegans with Enzo’s PROTEOSTAT® AGGREGATION ASSAY kit to detect bacteria-induced changes in the protein folding environment resulting in aggregation and pathogenicity. Overall, the Czyz lab reveals that detrimental bacteria disrupt host proteostasis and contribute to disease pathogenesis in the C. elegans model.

Who should attend this webinar?
Anyone interested in neurological health and disease.

Why should you attend this webinar?
Whether you are a scientist, a student, or a curious citizen, this webinar will exemplify real world applications of cutting edge technology for the advancement of neuroscience and treatment of neurodegenerative diseases by identifying underlying causes of protein misfolding.

Presented by: Dr. Daniel Czyz
Assistant Professor
University of Florida

Topic: Neuroscience