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

Abstract

More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP’s catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults

“…One of the gene subsets most commonly downregulated across INSTIs were those associated with extracellular matrix interactions and cell motility, including ADAM metallopeptidases, laminins and collagens, and C3 and CXCL12 , classic pro-inflammatory genes with known roles in neural structure and development ( Figures 6A–C, E ). These observations are consistent with a recent report relating integrase inhibitors’ ability to impair matrix metalloproteinase function with the frequent–yet inconclusive–clinical reports of structural defects in the developing CNS when exposed to INSTIs in utero ( Xu et al, 2017 ; Bade et al, 2021 ; Foster et al, 2022 , 2023 ; Zizioli et al, 2023 ). The majority of the significant differentially expressed genes altered by EVG were shared with RAL ( Figure 6D ), and several of the unique RAL genes also involved morphogenesis and TGF-β signaling.…”

“…MEA experiments indicated that EVG had a greater impact on cell viability than RAL, as previously reported in rodent models (Stern et al, 2018b;Smith et al, 2022). The shared transcriptomic trend of downregulated ECM-associated genes is the first demonstration in neurons of matrix interaction deficits consistent with those INSTIIs induced in myeloid cells, and may be particularly relevant in a developing neuronal model (Bade et al, 2021;Foster et al, 2023). In LPS-treated microglia supernatant experiments, drastic reduction of coordinated firing was consistent with down regulation of AMPA and NMDA receptor genes, which has been previously reported in CNS cells exposed to LPS-induced inflammation (Pellegrini-Giampietro et al, 1994;Zubareva et al, 2020).…”

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

“… 37 , 38 Higher homocysteine levels have been reported in people living with HIV, although specific investigations in the context of DTG use are lacking. 35 DTG has also been shown to inhibit matrix metalloproteinases (MMPs), 39 , 40 which play an important role in a wide range of developmental processes including vascular remodelling, angiogenesis, and establishment of the blood–brain barrier. 41 , 42 …”

“…37,38 Higher homocysteine levels have been reported in people living with HIV, although specific investigations in the context of DTG use are lacking. 35 DTG has also been shown to inhibit matrix metalloproteinases (MMPs), 39,40 which play an important role in a wide range of developmental processes including vascular remodelling, angiogenesis, and establishment of the blood-brain barrier. 41,42 We observed no significant differences in foetal weight, placental weight, litter size, foetal viability, or resorption rates between control and DTG groups under folate-deficient conditions.…”

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

“…ARVs reduce mother-to-child-transmission of HIV ( Schnoll et al, 2021 ) and drugs that produce synapse loss might have neurodevelopmental consequences ( Foster et al, 2023 ). Umbilical cord-to-maternal plasma concentration ratios for BIC, ETV, and NFV are 1.46, 0.52, and 0.19, respectively ( Mulligan et al, 2016 ; Eke et al, 2019 ; Bukkems et al, 2021 ).…”