Synergistic Effect of Nicotine and Antiretrovirals on Placental Development

About This Grant

Project Summary Background: The number of women living with human immunodeficiency virus type 1 (HIV-1) getting pregnant while on antiretroviral therapy is steadily rising. This is due to the growing availability of antiretroviral drugs (ARVs) at affordable access worldwide. Each year, more than a million women LWH have given birth while on ART. Although ART has significantly reduced the rate of vertical HIV-1 transmission to less than 1%, risks of adverse events on fetal outcomes linked to in utero ARVs exposure remain a major concern. Studies showed that HIV-1-exposed uninfected (HEU) children are at increased risk for preterm delivery, infectious morbidity, mortality, immune abnormalities, and impaired growth or neurodevelopment; yet there are gaps in understanding of how in utero ARVs exposures may impact placental development, the key regulator of fetal growth. One of the major reasons behind this limitation include co-morbidities complicating the interpretations. There is a substantial knowledge gap about the effects of comorbid ARV’s and substance use on placenta. Several addictive agents are commonly used by pregnant woman LWH, however, globally nicotine exposure through smoking or tobacco use remains as one of the major co-morbidities. Smoking is an independent risk factor for adverse fetal outcomes, such as preterm delivery, low birth weight, and intrauterine growth restriction. However, whether and how, ARVs and nicotine together produce synergistic effect to exacerbate adverse effects on placental development affecting pregnancy outcomes is unknown. Objective: Uncover how co-exposure of nicotine exacerbate ARVs-linked adverse effects on placenta development and employ long-acting (LA) delivery means to alleviate the impact of co-morbidity by attenuating ARVs-linked adverse effects. For ARVs, the focus will be on commonly prescribed and first-line integrase strand transfer inhibitors (INSTIs). Preliminary data: We observed that dolutegravir (DTG) reduced MMP-2 activity and HIF-1α protein accumulation under both normoxic and hypoxic conditions in cultured trophoblasts, reducing migration abilities. Moreover, nicotine further exacerbated the effect of DTG on HIF-1α protein accumulation. DTG-induced abnormalities in these proteins influenced impairment in placenta vasculature development in rodent model. Hypothesis: Synergistic effects of INSTI and nicotine on MMPs and HIF-1α impairs placental morphology and vasculature development. Research Strategy: (1) Assessment of effects of co-exposure of INSTIs and nicotine on trophoblasts functions and associated alterations in global proteomic profile; (2) Determine synergistic impact on placental development in a rodent model; and (3) Evaluate injectable long-acting delivery means for protective outcomes. Expectations: Nicotine exacerbates adverse impact of INSTIs on placenta development and that long-acting delivery approach will attenuate the impact of co-morbidity by attenuating INSTIs’ exposure to placenta.