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
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".