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

> **NIH HD R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2026 · $567,305

## Abstract

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 impro

## Key facts

- **NIH application ID:** 11320735
- **Project number:** 5R01HD115482-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Aditya N Bade
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HD
- **Fiscal year:** 2026
- **Award amount:** $567,305
- **Award type:** 5
- **Project period:** 2024-05-15T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11320735

## Citation

> US National Institutes of Health, RePORTER application 11320735, Integrase Inhibitors during pregnancy and Neurodevelopmental Outcomes: Underlying Mechanism and Therapeutic Intervention (5R01HD115482-03). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11320735. Licensed CC0.

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