Integrase Inhibitors during pregnancy and Neurodevelopmental Outcomes: Underlying Mechanism and Therapeutic Intervention

Project Summary Background: Dolutegravir (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 the roll out of generic DTG-based regimen, its inclusion in national treatment guidelines and rising pretreatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in resource limited countries, 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, 2021). However, during recent years, growing data from clinical and pre-clinical studies have suggested that DTG is associated with developmental neurologic abnormalities. Thus, concerns emerged for the usage of DTG-based regimens in pregnant women or those of child-bearing age. Knowledge gap: Underlying mechanism for DTG-associated developmental neurotoxicity (prenatal and postnatal), particularly in babies born without structural, brain or spinal cord, malformations, remains unknown. Moreover, therapeutic measures to enhance the DTG use for safer medication during pregnancy are infancy. 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 CNS and inhibit MMPs activity during the critical period of brain development. Further postnatal evaluation of brain health in mice pups following in utero DTG exposures identified neuroinflammation, neuronal damage and behavioral deficits. These data demonstrated an association between DTG dysregulation of MMPs activities during gestation and consequent neurotoxicity. Hypothesis: We posit that DTG inhibition of MMPs activities impairs pre- and post-natal neurodevelopment and offered long- acting approaches will serve to improve drug’s therapeutic benefits during pregnancy. Research Strategy: (1) Determine longitudinal dose-dependent effect of DTG on MMPs activity and/or expression in brain of embryos and early age postnatal pups and identify impact of such inhibitions in MMPs activity on neuronal development. (2) Investigate postnatal neurobehavioral outcomes that occurs across mouse development from adolescence to young age following gestational DTG exposure. (3) Utilize long-acting poloxamer-based DTG nanoformulations to provide potential delivery means to attenuate drug-associated neurotoxicity. (4) Establish scientific exchange with clinical study to establish clinical relevance. Outcome: Successful outcome of the proposal will significantly advance the basic and clinical research fields in understanding the theory of DTG inhibition of MMPs activities as the underlying mechanism for DTG-associated developmental neurotoxicity, impaired neurobehavioral outcomes, and provide long-acting poloxamer-encapsulated DTG nanoformulations as potential delivery means to improve the safety and therapeutic profile of DTG during pregnancy.