Fig. 8.

Probable mechanistic pathways by which HIV-exosomes can perturb normal mitochondrial dynamics and cause initial HBMVECs dysfunction leading to brain pathologies. HIV-exosomes are readily taken up by primary HBMVECs and cause dysfunction and damage via multiple pathways involving mitochondria. The following experimental observations were noticed: (1) primary HBMVECs exposed to HIV-exosomes produced cellular ROS that subsequently induced mitochondrial depolarization, and hyperfusion resulting in brain endothelial dysfunction (indicated by light blue arrows). (2) Similarly, HIV-exosomes also generated mitochondrial ROS, which in turn, caused endothelial dysfunction by inducing mitochondrial depolarization, and hyperfusion (indicated by pink arrows). (3) HIV-exosomes could be developed endothelial dysfunction by ROS-independent pathways (indicated by dotted green arrows). Viral/cellular factor(s) could be directly dysregulated the mitochondrial membrane potential (3A), or mitochondrial fission/fusion machinery (3B). Dark blue arrows indicated the release of exosomes by the cells. The black and orange arrows indicated the possible crosstalk within mitochondrial depolarization, and hyperfusion for the development of endothelial dysfunction