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

Schnoll, Jordan G.; Temsamrit, Brian; Zhang, Dongke; Song, Hongjun; Ming, Guo‐li; Christian, Kimberly M.

doi:10.1007/s11481-019-09880-z

Cited by 31 publications

(36 citation statements)

References 124 publications

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“…With the widespread global use of DTG-based regimens and noted ADE in clinical and preclinical studies, defining in utero effects of drug on fetal development is timely. This includes the mechanism(s) of action on the developing CNS [2,[9][10][11][12][13]. Prior works focused on determining relationships between folate levels or transport pathways and DTG-associated birth defects failed to conclusively generate any cause and effect relationships [11,[56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

“…Both clinical and preclinical studies observed the risk of NTD's following in utero DTG exposure and stressed the importance of identifying unknown potential adverse drug effects (ADEs) [9][10][11]. These include any injuries resulting from in utero DTG exposures, including biological, physiological, metabolic, or functional harm to the fetal central nervous system (CNS), particularly in babies born without structural, brain or spinal cord, malformations [12,13]. Recently, the Surveillance Monitoring for ART Toxicities (SMARTT), an observational study, reported associations between in utero DTG exposures and neurologic abnormalities in newborns and during development [2].…”

Section: Introductionmentioning

confidence: 99%

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Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

et al. 2021

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Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme’s catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

et al. 2021

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“…First isolated in 1983, the HIV is a retrovirus virus that causes acquired immune deficiency syndrome (AIDS) ( 48 ). The main modes of transmission of the virus are sexual transmission, blood transmission, and mother-to-child vertical transmission ( 49 , 50 ).…”

Section: Brain Organoids As Models For Hiv Infectionmentioning

confidence: 99%

Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases

Peng

Kong

et al. 2022

Front. Immunol.

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Brain organoids, or brainoids, have shown great promise in the study of central nervous system (CNS) infection. Modeling Zika virus (ZIKV) infection in brain organoids may help elucidate the relationship between ZIKV infection and microcephaly. Brain organoids have been used to study the pathogenesis of SARS-CoV-2, human immunodeficiency virus (HIV), HSV-1, and other viral infections of the CNS. In this review, we summarize the advances in the development of viral infection models in brain organoids and their potential application for exploring mechanisms of viral infections of the CNS and in new drug development. The existing limitations are further discussed and the prospects for the development and application of brain organs are prospected.

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“…Gliogenesis and myelinisation start around week 22 and continue after birth until adulthood. 13 During gestation, fetal neurological development is extremely sensitive to maternal exposures, such as infections, toxins, and illicit drugs, which are associated with a range of developmental disorders, depending on type and timing of exposure. 14,15 Children who are HIV-exposed and uninfected: a research priority…”

Section: Fetal Neurological Developmentmentioning

confidence: 99%

Neurological development of children who are HIV‐exposed and uninfected

Toledo

Côté

Adler

et al. 2021

Develop Med Child Neuro

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Widespread use of antiretroviral drugs for pregnant/breastfeeding females with human immunodeficiency virus (HIV) has led to declining vertical transmission. Despite being HIV‐uninfected, the increasing number of children who are HIV‐exposed and uninfected (CHEU) often present with developmental alterations. We review seminal and recent evidence on the neurological development of CHEU and associations with early life HIV/antiretroviral exposure. Our conceptual model highlights the numerous exposures and universal risk factors for CHEU developmental disorders. Early studies suggest a significant association between HIV exposure and neurological abnormalities, varying according to the burden of HIV‐specific exposures and other risk factors. More recent observations from the modern era are inconsistent, although some studies suggest specific antiretrovirals may adversely affect neurological development of CHEU. As the CHEU population continues to grow, alongside simultaneous increases in types and combinations of antiretrovirals used in pregnancy, long‐term monitoring of CHEU is necessary for understanding the effects of HIV/antiretroviral exposure on CHEU developmental outcomes. Evidence on the neurological development of children who are human immunodeficiency virus (HIV)‐exposed and uninfected (CHEU) is synthesized. Comparisons are made to children who are HIV‐unexposed, across treatment eras and settings, and by antiretroviral drug regimens and drug classes. CHEU exposures are complex and include HIV‐specific and universal risk factors which may affect development during the early years of life.

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

Cited by 31 publications

References 124 publications

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases

Neurological development of children who are HIV‐exposed and uninfected

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