Physical and Metabolic Integrity of the Blood-Brain Barrier in HIV Infection: A Special Focus on Intercellular Junctions, Influx and Efflux Transporters and Metabolizing Enzymes

The advent of highly active antiretroviral therapy has significantly reduced morbidity and mortality in human immunodeficiency virus (HIV) infection. Despite this reduction, complete eradication of HIV from the human body is not feasible in the nearly seen future. The central nervous system (CNS) is protected from blood-borne substances by a subtle structure of vascular endothelia known as blood-brain barrier (BBB). The BBB expresses transporters and metabolizing enzymes that modulate drug permeability in the CNS. This paper reviews the changes of the BBB phenotype as a physical and metabolic barrier in HIV infection. The effects of HIV and its proteins on intercellular junctions, influx and efflux transporters and metabolizing enzymes expressed at the BBB are reviewed. In HIV infection, the integrity of the BBB is severely compromised which often leads to serious neuropathological manifestations in the CNS. HIV and its proteins affect signaling pathways leading to oxidative stress, induction of matrix metalloproteinases and cytokines, down-regulation of different structural components of intercellular junctions, transporters and metabolizing enzymes. Taken together, HIV infection severely disrupts the integrity of the BBB and homeostasis of the CNS leading to modulation of drug disposition in the CNS and neurotoxicity. Applying knowledge of these mechanisms may lead to new therapeutic avenues to reduce neurological complications of HIV infection in the CNS.