Placental Insulin-Like Growth Factor-1 Receptor, Protein Kinase B and Mammalian Target of Rapamycin are Downregulated in HIV-1 Positive Women on Antiretroviral Drugs

Abstract

HIV-1 and ARV drugs uptake during pregnancy may change placental phenotype during pregnancy affecting fetal growth. We investigated the influence of maternal HIV-1 and ARV drugs on expression of placental genes important for fetus growth. A total 51 HIV-1 positives and 46 HIV-1 negative pregnant women were studied. Placental gene expression changes of insulin-like growth factor receptor 1 (IGF-1) R, mammalian target of rapamycin (mTOR), protein kinase B (AKT-1), sodium-coupled neutral amino acid transporters (Slc38a1, Slca38a2, Slc38a4), inhibin A, adrenomedullin and 11 beta-Hydroxysteroid dehydrogenase type (HSD)-2 were assessed by RT-qPCR. There was a significant decrease in mRNA expression of placental IGF-1R, mTOR, and AKT-1 in HIV-1 positive placentas compared to controls (p < 0.0001). There was also significant upregulation of an antiangiogenic molecule, inhibin A and downregulation of angiogenic molecule adrenomedullin in HIV-1 positive placenta (all p < 0.0001). However, the mRNA expression of placental Slc38a1 and Slca38a2 was higher in both HIV-1 positive and negative women delivering LBW babies compared to controls (p < 0.0001). The placental mRNA expression of 11 β-HSD-2 increased by 17 folds in HIV-1 negative and by 3.8 folds in HIV-1 positive women delivering LBW babies. IGF-1-P13-AKT-1-mTOR signaling pathway is dysregulated in placenta of HIV-1 positive women on ARV drugs. Higher mRNA expression levels of inhibin A and lower levels of adrenomedullin occur in placenta of HIV-1 positive women delivering LBW babies. ARV drugs and HIV-1 may be involved in the disruption of vascular tone of the placenta and therefore placental perfusion.

Keywords: Pregnant women, HIV-1, ARV drugs, Placental IGF-1-AKT-1-mTOR signaling, inhibin A, adrenomedullin, amino acid transporters.