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Evaluating Neurodevelopmental Consequences of Perinatal Exposure to Antiretroviral Drugs: Current Challenges and New Approaches

  • Jordan G. Schnoll
  • Brian Temsamrit
  • Daniel Zhang
  • Hongjun Song
  • Guo-li Ming
  • Kimberly M. ChristianEmail author
Invited Review

Abstract

As antiretroviral therapy (ART) becomes increasingly affordable and accessible to women of childbearing age across the globe, the number of children who are exposed to Human Immunodeficiency Viruses (HIV) but remain uninfected is on the rise, almost all of whom were also exposed to ART perinatally. Although ART has successfully aided in the decline of mother-to-child-transmission of HIV, the long-term effects of in utero exposure to ART on fetal and postnatal neurodevelopment remain unclear. Evaluating the safety and efficacy of therapeutic drugs for pregnant women is a challenge due to the historic limitations on their inclusion in clinical trials and the dynamic physiological states during pregnancy that can alter the pharmacokinetics of drug metabolism and fetal drug exposure. Thus, much of our data on the potential consequences of ART drugs on the developing nervous system comes from preclinical animal models and clinical observational studies. In this review, we will discuss the current state of knowledge and existing approaches to investigate whether ART affects fetal brain development, and describe novel human stem cell-based strategies that may provide additional information to better predict the impact of specific drugs on the human central nervous system.

Graphical Abstract

Approaches to evaluate the impact of drugs on the developing brain. Dysregulation of the developing nervous system can lead to long-lasting changes. Integration of data from animal models, clinical observations, and cell culture studies is needed to predict the safety of therapeutic antiretroviral drugs during pregnancy. New approaches include human induced pluripotent stem cell (iPSC)-based 2D and 3D models of neuronal networks and brain regions, as well as single cell profiling in response to drug exposure.

Keywords

Neurodevelopment antiretroviral drugs organoids iPSCs 

Notes

Acknowledgments

This work was supported grants from National Institutes of Health (R35NS097370 and U19AI131130 to G-l.M.) and (R21MH118037 to K.M.C.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Biochemistry and Molecular Biophysics Graduate GroupUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Institute for Regenerative MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.The Epigenetics InstituteUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Department of Cell and Developmental BiologyUniversity of PennsylvaniaPhiladelphiaUSA
  6. 6.Department of Psychiatry, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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