Breast milk lacking anti-human immunodeficiency virus activity promotes exocytosis of HIV from the mother's mammary epithelium and transcytosis of virus via the infant's tonsil and intestinal epithelial cells

Abstract

Although mammary epithelial cells (MECs) and breast milk facilitate mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV-1), the mechanisms underlying these observations remain poorly understood. In this work, we explored the molecular mechanisms associated with HIV-1 transcytosis through MECs and the role of breast milk in promoting viral transmigration through infant tonsils and intestinal epithelia. Our findings revealed that transfer of cell-free HIV-1 from the maternal circulation into breast milk is mediated by its basolateral-to-apical transcytosis through polarized MECs that function as a blood-milk barrier. While breast milk samples from 76 % of the HIV-negative donors contained factors that inactivated the virus by disrupting viral envelope glycoprotein gp120, thereby preventing MTCT, the remaining breast milk samples that were incapable of inactivating HIV-1 nonetheless induced viral exocytosis from the apical surface of MECs. Interestingly, these otherwise inactive breast milk samples also promoted a substantial increase in viral internalization, transcytosis, and exocytosis from infant tonsils and gut epithelial cells, ultimately leading to infection of virus-susceptible subepithelial cells. We determined that elevated calcium concentrations in breast milk play an important role in promoting HIV-1 entry, transcytosis, and exocytosis from infant tonsil and gut epithelial cells via activation of protein kinase C and calcium sensor synaptotagmin 7. Collectively, these findings suggest that breast milk samples from different sources may either promote or prevent HIV MTCT by several different mechanisms. Further investigation of this phenomenon may ultimately improve our understanding of the molecular pathogenesis of HIV MTCT and suggest new strategies for its prevention.

Keywords: Breast milk; Endocytosis; Exocytosis; HIV mother-to-child transmission; Human immunodeficiency virus; Mammary epithelial cells; Protein kinase C; Synaptotagmin 7; Transcytosis.