We hypothesize that conditional expression of the HIV-1 protein transactivator of transcription (Tat) and exposure to opioids in animal models synergistically induces changes analogous to HAND, including deficits in neurophysiology (increased reactive oxygen species (ROS), and reduced Brain-Derived Neurotropic Factor (BDNF) and mitochondrial biogenesis) and behavior (increased drug-seeking and depression-like behaviors, while impairing learning and memory performance). This evidence concerns the gene TAT and major depressive disorder.