The oral mucosa immune environment and oral transmission of HIV/SIV

Abstract

The global spread of human immunodeficiency virus (HIV) is dependent on the ability of this virus to efficiently cross from one host to the next by traversing a mucosal membrane. Unraveling how mucosal exposure of HIV results in systemic infection is critical for the development of effective therapeutic strategies. This review focuses on understanding the immune events associated with the oral route of transmission (via breastfeeding or sexual oral intercourse), which occurs across the oral and/or gastrointestinal mucosa. Studies in both humans and simian immunodeficiency virus (SIV) monkey models have identified viral changes and immune events associated with oral HIV/SIV exposure. This review covers our current knowledge of HIV oral transmission in both infants and adults, the use of SIV models in understanding early immune events, oral immune factors that modulate HIV/SIV susceptibility (including mucosal inflammation), and interventions that may impact oral HIV transmission rates. Understanding the factors that influence oral HIV transmission will provide the foundation for developing immune therapeutic and vaccine strategies that can protect both infants and adults from oral HIV transmission.

Fig. 1. Oral mucosa immune activation and HIV susceptibility

The buccal mucosa, non-keratinized stratified squamous epithelium that lines the inner cheek, is shown during exposure to an HIV/SIV quasispecies (variation in virus color reflects the variability in viral genetic sequence) under inflammatory (left side) and immune quiescent (right side) conditions. HIV/SIV can cross through the epithelium either through transcytosis or by migrating between disrupted cell-cell junctions, which can occur in response to inflammatory stimuli. This disruption of tight junctions results in an increase in the number of viral variants that successfully enter the lamina propria. Langerhans cells, which facilitate virus transfer to productively infected cells, reside in the basal layer of the epithelium and may increase in response to inflammatory stimuli. CD4⁺ HIV/SIV target cells of the lamina propria, primarily macrophages and T cells, can express variable levels of the HIV/SIV co-receptor CCR5. Notably, CCR5 expression is enhanced, particularly on T cells, under inflammatory conditions, while CCR5-expressing cells are rare in quiescent mucosa. CD4+ cells with high CCR5 expression are most readily infected with HIV, resulting in more productively-infected cells in inflamed conditions and a paucity of infected cells in quiescent conditions. These infected cells then produce additional virus and facilitate dissemination of the virus throughout the systemic circulation, leading to the establishment of productive HIV/SIV infection.