In this review, we summarize some recent findings regarding the likely mechanisms by which HIV-1 uses the testis as a sanctuary site for evading the effects of antiviral drugs from reaching the testis, due to the presence of the blood-testis barrier. This discussion also sheds insights into the possibility of eradicating the small viral pool in the testis behind the blood-testis barrier in future functional studies. These findings also bridge the knowledge gap of eradicating viral particles hiding behind the blood-brain barrier in the brain since it is anticipated that the blood-tissue barriers, namely the blood-testis and the blood-brain barriers, are utilizing similar mechanisms to regulate the dynamic nature of their tight junctions.