Nucleoside and HIV Drug Transport at the Blood-Testis Barrier

Abstract

The immune-reactive sperm are kept separate from the body by epithelial barriers such as the blood-testis barrier (BTB). While these barriers are beneficial for the protection of sperm from toxicants, they can make treating these areas difficult due to preventing the entry of pharmacological agents. This is especially an issue in the treatment of HIV and Ebola infection based on the ample evidence that these viruses are able to survive and spread from within the male genital tract (MGT), but only a few antiviral drugs are known to access the MGT. Transporters that line the epithelial barriers of the MGT, especially the BTB, are important for determining whether or not a drug is able to penetrate into the MGT through transepithelial transport. Several nucleoside analogs (NSA), which are used to treat HIV infection and leukemias, are known to be able to accumulate in seminal plasma, which makes them a useful tool for understanding transepithelial transport for the BTB. The purpose of these studies is to characterize the transport profile for the MGT, in particular the BTB, to gain a better understanding of how xenobiotics, especially ones based on nucleosides, can access the MGT. The chief finding of this work is the discovery of a transepithelial transport pathway expressed by Sertoli cells that allows for the entry of nucleosides (necessary for germ cell development) and NSA into the MGT. This pathway depends on equilibrative nucleoside transporter (ENT) 1 uptake and ENT2 efflux and occurs in both rats and humans. These studies provide the foundation for being able to predict the penetration of novel drugs into the MGT.