Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

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.

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

“…Although few studies have addressed placental transfer of CAB and BIC, evidence does suggest that these INSTIs also cross the placental barrier (Pencole et al, 2020;Bukkems et al, 2021;Le et al, 2022). Our previous work investigated pharmacokinetic (PK) and biodistribution (BD) of DTG during pregnancy in mice and confirmed that DTG levels are detectable in brain tissues of embryos following daily oral administration at supratherapeutic dosage (Bade et al, 2021). Our work validated clinical reports of high placental transfer of DTG and was the first to show drug levels in the fetal developing brain during gestation.…”

“…Cells were plated at a density of 1 × 10 6 in 12 well plates and treated with phorbol-12-myristate-13-acetate (PMA) for 24 h. This was done to promote cell differentiation to stimulate MMP secretion. Following PMA treatment, cells were treated with DTG, CAB, BIC, or DOX at concentrations of 25, 50, 75, or 100 µM or control vehicle for 24 h. In our previous study, no DTG-induced cytotoxicity was recorded in PMA-stimulated THP-1 cells up to 100 µM ( Bade et al, 2021 ). Thus, for comparative assessments among different INSTIs (DTG, BIC, and CAB) and DOX (positive control) drug concentrations of up to 100 µM were utilized.…”

“…EVG, BIC or CAB are not recommended during pregnancy due to limited safety data ( The U.S. Department of Health and Human Services, 2015 ). Recently DTG was found to be potentially associated with birth defects (NTDs) and postnatal neurodevelopmental abnormalities ( Hill et al, 2018 ; Cabrera et al, 2019 ; Zash et al, 2019 ; Crowell et al, 2020 ; Mohan et al, 2020 ; Bade et al, 2021 ). Given the widescale usage of DTG as a part of first-line regimens worldwide ( Hill et al, 2018 ; Dorward et al, 2018 ; World Health Organization (WHO), 2018 ; The Lancet, 2020 ) and emerging potent INSTIs such as BIC and CAB, uncovering any INSTIs-associated adverse effects and thus, the underlying mechanisms is of importance.…”

“…No other biomarker linked to INSTI drug-induced adverse events has been explored. We demonstrated that DTG is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) ( Bade et al, 2021 ). MMPs are known to play a role in many neurodevelopmental processes, including, but not limited to axonal growth and guidance, synaptic development and plasticity ( Ethell and Ethell, 2007 ; Agrawal et al, 2008 ; Fujioka et al, 2012 ; Reinhard et al, 2015 ; De Stefano and Herrero, 2017 ).…”

“…MMPs are known to play a role in many neurodevelopmental processes, including, but not limited to axonal growth and guidance, synaptic development and plasticity ( Ethell and Ethell, 2007 ; Agrawal et al, 2008 ; Fujioka et al, 2012 ; Reinhard et al, 2015 ; De Stefano and Herrero, 2017 ). Therefore, dysregulation of their activities could affect fetal neurodevelopment ( Reinhard et al, 2015 ; Bade et al, 2021 ). Docking assessments against five MMPs showed that DTG binds to Zn++ at the catalytic domain of an MMP to inhibit the enzyme’s activity.…”