Figure 2.

Synergistic impact of HIV-1 infection and methamphetamine (METH) use on the blood–brain barrier (BBB). The main component of the BBB is endothelial cells, which are bridged by tight junction (TJ) protein complexes. Illustrated are four critical TJ proteins that are synergistically affected by comorbid HIV-1 infection and METH: occludin, zonula occludens 1 (ZO-1), claudin-5, and junctional adhesion molecule-A (JAM-A). In addition, HIV-1 infection and METH synergistically affect carrier-mediated transport across the BBB by impairing the functions of P-glycoprotein (P-gp) and two glucose transport proteins, GLUT1 and GLUT3. METH and HIV-1 also synergistically induce oxidative stress via activation of transient receptor potential melastatin 2 (TRPM2) channels in endothelial cells. The combination of METH and HIV-1 infection induces excessive production of reactive oxygen species (ROS) and impairs the defensive abilities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD). Elevated activity of matrix metalloproteinase-9 (MMP-9) leads to the degradation of the basement membrane (BM). Increased BBB permeability due to degradation of TJs and BM proteins may facilitate transmigration of HIV-1-infected monocytes and CD4+ T cells into the brain. METH enhances HIV-1 replication in HIV-1 infected CD4+ T cells, likely stimulating transmigration of infected immune cells across the BBB. HIV-1 replication can be enhanced by METH, contributing to increased viral load in the brain. Created with BioRender.com.