The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research

Abstract

The advent of highly active antiretroviral therapy (HAART), which constitutes HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors, has dramatically reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) infection in resource-rich countries. However, this disease still kills several million people each year. Though the reason for therapeutic failure is multi-factorial, an important concern is the treatment and control of HIV within the central nervous system (CNS). Due to the restricted entry of anti-HIV drugs, the brain is thought to form a viral sanctuary site. This not only results in virological resistance, but also is often associated with the development of complications such as HIV-associated dementia. The CNS delivery of anti-HIV drugs is limited by the blood-brain and blood-CSF interfaces due to a combination of restricted paracellular movement, powerful metabolic enzymes and numerous transporters including members of the ATP binding cassette (ABC) and solute carrier (SLC) superfamilies. A better appreciation of the transporters present at the brain barriers will prove a valuable milestone in understanding the limited brain penetration of anti-HIV drugs in HIV and also aid the development of new anti-HIV drugs and drug combinations, with enhanced efficacy in the CNS. This review aims to summarise current knowledge on the transport of anti-HIV drugs across the blood-brain barrier and the choroid plexus, as well as provide recommendations for future research.

Fig. 1

Permeation mechanisms across the BBB: (1) paracellular diffusion between the cells of the capillary endothelium. (2) Transcellular diffusion; solutes with sufficient lipid solubility may passively diffuse through the cell membranes of the endothelial cells and enter the brain. (3) Carrier-mediated transport of more hydrophilic molecules is via SLCs inserted into the luminal and/or abluminal membrane. These may be (a) facilitated bi-directional carriers operating in the direction of the concentration gradient, (b/c) uni-directional into or out of the cell (d) co-transporters/exchangers co-transporting or exchanging another solute or ion in the same or opposite direction. (4) Active efflux carriers (ABC transporters) may pump out a wide range of passively penetrating solutes either from the cytoplasmic compartment or directly from the cell membrane. (5) Transcytosis can also occur which may be non-specific (fluid phase, very limited at the BBB) or specific. Specific mechanisms include absorptive-mediated transcytosis (AMT), which involves an electrostatic interaction between a positively charged substance and the negatively charge plasma membrane surface, or receptor-mediated transcytosis (RMT), which involves a receptor (Rc) and is highly selective for specific molecules.