Functional Expression and Regulation of Drug Efflux Transporters and Drug Metabolic Enzymes in the Testis and Circulating T-cells: Relevance to HIV-1 Pharmacotherapy

Despite significant advances in human immunodeficiency virus (HIV) pharmacotherapy with the implementation of combination antiretroviral therapy (ART), HIV persistence in cellular reservoirs and tissue sanctuary sites is a major obstacle preventing the eradication of the virus. Suboptimal antiretroviral drug (ARV) concentrations reached in several anatomic sites such as the brain, testis, and gut-associated lymphoid tissues, could contribute in part, to persistent HIV infection. Biological membrane-bound ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, as well as drug metabolic enzymes, are known to interact with numerous ARVs, and as a result, could affect their distribution at sites of infection. Particularly, ABC drug efflux transporters and drug metabolic enzymes could reduce ARV concentrations in HIV target cells and tissues. The testis is recognised as an HIV sanctuary site, displaying subtherapeutic antiretroviral concentrations and persistent HIV infection. Furthermore, T-cells are the major cell types contributing to the HIV reservoir. Therefore, the objectives of this thesis were to: i) investigate the role of transcription factors i.e., pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the regulation of drug efflux transporters at the BTB, ii) assess the functional expression of ABC drug efflux transporters and drug metabolic enzymes in various human testicular and circulating T-cell subsets, and iii) examine the expression of drug efflux transporters, and their regulation by the mammalian target of rapamycin (mTOR), in T-cells exposed to HIV-1 envelope glycoprotein (recombinant gp120IIIB) or pseudotype virus (pHIVNL4-3). We obtained novel data demonstrating PXR- and CAR-mediated upregulation of the functional expression of drug efflux transporters at the mouse BTB. We further demonstrated that drug efflux transporters and metabolic enzymes are functionally expressed in T-cell subsets infiltrating the human testis, suggesting their potential roles in restricting ARV permeability in this tissue. Finally, we provided evidence that ABC drug efflux transporters are upregulated in T-cells exposed to HIV via the mTOR signaling pathway. Understanding the roles and regulation of drug efflux transporters and metabolic enzymes in ARV disposition in HIV cell reservoirs and tissue sanctuaries is critical to overcome the challenge of suboptimal drug penetration at these sites.

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