CROI 2015 Program and Abstracts

Oral Abstracts

*Values are presented as median (range) and p values are for Mann-Whitney U test. Conclusions: The clinical relevance of these findings is uncertain, since dose-reduction of EFV in non-pregnant adults was previously not associated with increased risk of virological failure. Nevertheless, the impact of pharmacogenetic variability on mother-to-child transmission of HIV should be further studied. 534 Antiretroviral Drug Transporters and Metabolic Enzymes in Human Testicular Tissue Billy Huang 1 ; Md.Tozammel Hoque 1 ; Mohammad-Ali Jenabian 3 ; KishandaVyboh 2 ; Nancy Sheehan 2 ; Pierre Brassard 4 ; Maud Bélanger 4 ; Nicolas Chomont 5 ; Jean-Pierre Routy 2 ; Reina Bendayan 1 1 University of Toronto, Toronto, Canada; 2 McGill University, Montréal, Canada; 3 Université du Québec à Montréal, Montréal, Canada; 4 Metropolitan Centre of Plastic Surgery, Montréal, Canada; 5 Vaccine and Gene Therapy Institute of Florida, Port St Lucie, FL, US Background: Previous studies have reported that HIV-1 is capable of both acute and persistent infection in the testes. The naturally restrictive environment in the testes due in part to the blood-testes-barrier (BTB), suggests that this barrier could restrict antiretroviral (ARV) penetration into this tissue and contribute to the formation of a viral sanctuary. This study aims to characterize drug transporters and metabolic enzymes expression and localization in the testes of uninfected and HIV-1-infected men receiving antiretroviral therapy (ART) in order to gain further insight on the factors regulating ARV disposition in this organ. Methods: Testicular tissues were collected from uninfected men (N=8) and HIV-1 infected men on ART (plasma viral load <50 copies/mL for at least 6 months prior to surgery, N=5) who underwent elective orchiectomy for gender reassignment surgery at the Metropolitan Centre of Plastic Surgery in Montreal. We selected four ATP-binding cassette (ABC) transporters, six solute-carrier (SLC) transporters and two cytochrome P450 (CYP450) drug metabolic enzymes to study based on their relevance to ARV disposition, and assessed their gene and protein expression as well as tissue localization. Results: In testicular tissues, we found that MRP2 and OATP2B1 were highly expressed at the mRNA level, BCRP showed moderate expression, while expression of P-gp, MRP1, OATP1A2, OATP1B1, OAT1, OCT1, CNT1, ENT2, CYP2D6 and CYP3A4 were low. However, we were able to detect robust protein expression for all transporters and metabolic enzymes analysed with the exception of OATP1A2 and OCT1. Overall, gene and protein expression did not differ significantly between the uninfected and ART-treated HIV-1-infected men. Our fluorescence microscopy results also indicate that transporters and metabolic enzymes are not limited to BTB localization but can be found throughout the testicular tissue. Conclusions: It has been well documented that drug transporters and metabolic enzymes are capable of interacting with many commonly used ARVs, and could significantly affect drug disposition into tissues, especially at key blood-tissue barriers such as the blood-brain barrier. Our data are the first to demonstrate protein expression and localization of key drug transporters and metabolic enzymes in the testes of ART-treated HIV-1 infected men. Their presence suggests the testes are a complex pharmacological compartment that could limit the penetration of several ARVs in this tissue. ( Supported by CIHR and OGS)