Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone

Shreya H Dhume; Kayode Balogun; Ambalika Sarkar; Sebastian Acosta; Howard T J Mount; Lindsay S Cahill; John G Sled; Lena Serghides

doi:10.3389/fnmol.2024.1376681

Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone

Front Mol Neurosci. 2024 Apr 5:17:1376681. doi: 10.3389/fnmol.2024.1376681. eCollection 2024.

Authors

Shreya H Dhume^#¹, Kayode Balogun^#², Ambalika Sarkar¹, Sebastian Acosta³, Howard T J Mount⁴, Lindsay S Cahill^{5

6}, John G Sled^{6

7}, Lena Serghides^{1

3

8

9}

Affiliations

¹ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
² Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States.
³ Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, Department of Psychiatry and Physiology, University of Toronto, Toronto, ON, Canada.
⁵ Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, Canada.
⁶ Mouse Imaging Centre, Toronto Centre for Phenogenomics, Toronto, ON, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁸ Women's College Research Institute, Toronto, ON, Canada.
⁹ Department of Immunology, University of Toronto, Toronto, ON, Canada.

^# Contributed equally.

Abstract

Background: Combination antiretroviral therapy (ART) use in pregnancy has been pivotal in improving maternal health and reducing perinatal HIV transmission. However, children born HIV-exposed uninfected fall behind their unexposed peers in several areas including neurodevelopment. The contribution of in utero ART exposure to these deficits is not clear. Here we present our findings of neurocognitive outcomes in adult mice exposed in utero to ART.

Methods: Dams were treated with a combination of ritonavir-boosted atazanavir with either abacavir plus lamivudine (ABC/3TC + ATV/r) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC + ATV/r), or water as a control, administered daily from day of plug detection to birth. Offspring underwent a battery of behavioral tests that investigated motor performance and cognition starting at 6-weeks of age and ending at 8 months. Changes in brain structure were assessed using magnetic resonance imaging and immunohistochemistry. Expression of genes involved in neural circuitry and synaptic transmission were assessed in the hippocampus, a region strongly associated with memory formation, using qPCR.

Findings: Pups exposed to TDF/FTC + ATV/r showed increased motor activity and exploratory drive, and deficits in hippocampal-dependent working memory and social interaction, while pups exposed to ABC/3TC + ATV/r showed increased grooming, and deficits in working memory and social interaction. Significant volumetric reductions in the brain were seen only in the ABC/3TC + ATV/r group and were associated with reduced neuronal counts in the hippocampus. Altered neurotransmitter receptor mRNA expression as well as changes in expression of the neurotrophic factor BDNF and its receptors were observed in both ART-exposed groups in a sex-dependent manner.

Interpretation: In our model, in utero ART exposure had long-term effects on brain development and cognitive and motor outcomes in adulthood. Our data show that neurological outcomes can be influenced by the type of nucleoside reverse transcriptase inhibitor backbone of the regimen and not just the base drug, and display sex differences.

Keywords: HEU; HIV antiretrovirals; MRI; cognition; hyperactivity; memory; neurodevelopment; protease inhibitors.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work is funded by Canadian Institutes of Health Research (CIHR) grant #HAL 157984 (LS), and CANFAR grant #27010 (LS). LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. SHD is supported by a CIHR Postdoctoral Fellowship. KB was supported by a CTN Postdoctoral Fellowship.