Placenta models for HIV-1-ART-nicotine comorbidity research: advances and remaining challenges

Worldwide implementation of antiretroviral therapy (ART) for pregnant women living with human immunodeficiency virus type-1 (HIV-1) has markedly reduced mother-to-child HIV-1 transmission rate to less than one percent. Despite this benefit, adverse pregnancy outcomes remain a major concern. Placental deficits induced by antiretroviral drugs (ARVs) are increasingly recognized as a potential causative factor. Additionally, comorbid effects of substance use on placenta cannot be overstated. Addictive substances are commonly used by people living with HIV-1 (PLWH). However, globally, nicotine exposure through smoking or tobacco use remains a major comorbidity in PLWH. Yet, to date, whether and how, HIV-1, ARVs, and nicotine together exacerbate adverse effects on placenta and affect birth outcomes is unknown. Due to ethical concerns and impracticality of obtaining placenta tissues at different stages of pregnancy, appropriate experimental models that closely recapitulate in vivo placenta physiology are essential to define how HIV-1, ART, and nicotine independently or collectively affect placental development and functions. Herein, we provide a comprehensive review of the experimental placenta models that have been or are yet to be utilized to study placental comorbid pathobiology induced by HIV-1 infection, ART, and/or nicotine exposure. We emphasize how each model is used (or underused) to interrogate infection biology, pharmacokinetic profile, and toxico-pharmacologic mechanisms. Moreover, key limitations associated with each placenta model and necessary improvements for investigating HIV-1 and associated comorbidity are highlighted. Overall, this review seeks to educate both clinical and basic scientists on advances made, and remaining challenges in understanding comorbid effects of HIV-1-ART-nicotine on pregnancy outcomes using experimental placenta models.