Functional mechanism underlying Dolutegravir (DTG)-associated developmental CNS abnormalities: Inhibition of matrix metalloproteinases activities

项目总结

Project Summary Background: Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), currently recommended as both, first-line therapy and part of either switching or salvage regimens for the treatment of human immunodeficiency virus type-1 (HIV-1) infected patients. Due to the roll out of generic DTG-based regimen and its inclusion in national treatment guidelines in resource limited countries (RLCs), in just 5 years, 15 million HIV-1 infected people will be treated with DTG. This includes women of child-bearing age, who remain a significant infected population (UNAIDS data, 2020). However, during recent years, growing data from different clinical and pre- clinical studies have suggested that the DTG is associated with birth defects and with postnatal developmental neurologic abnormalities. Thus, concerns emerged for the usage of DTG-based regimens in pregnant women or those of child-bearing age. Knowledge gap: While clinical cohort studies identified risk of neurologic abnormalities in babies following in utero DTG-exposure, underlying mechanism for DTG-associated developmental neurotoxicity, particularly in babies born without structural, brain or spinal cord, malformations remains unknown. Our preliminary data: DTG was found to be a broad-spectrum inhibitor of MMPs. The drug was found to bind Zn++ at the catalytic domain, leading to inhibition of MMPs activities. Moreover, studies in pregnant mice showed that DTG can cross the placental barrier, accumulate in the fetal central nervous system (CNS) and inhibit MMPs activity during the critical period of fetal brain development. Further postnatal evaluation of brain health in mice pups following in utero DTG exposures identified neuroinflammation and neuronal damage. These data demonstrated an association between DTG dysregulation of MMPs activities during gestation and consequent neurotoxicity. Hypothesis: We hypothesize that DTG inhibition of MMPs activities during gestation impairs neurodevelopment. Research Strategy: (1) Determine dose-dependent enzyme inhibition kinetics of different drugs from INSTI class, which include DTG, bictegravir (BIC) and cabotegravir (CAB). (2) Determine longitudinal dose-dependent affect of DTG on MMPs function and expression in embryo CNS during gestation. (3) Identify the impact of MMPs inhibition by DTG on embryo neurodevelopmental physiological processes (angiogenesis and neurogenesis) during pregnancy. (4) Evaluate whether BIC and CAB also affect the MMPs activities and associated neurodevelopmental processes in vivo through same mechanism to assess the class effect. Research Team: We have assembled a multidisciplinary team with expertise in neuropathology, immunology, pharmaceutics, virology, and bioimaging to evaluate impact of in utero DTG and of other drugs from INSTI class exposure on the embryo brain development. Outcome: Successful outcome of the proposal will significantly advance the field in understanding the theory of DTG inhibition of MMPs activities during gestation as the underlying mechanism for DTG-associated developmental neurotoxicity and whether the same mechanism can be linked to other members of the INSTI class.