<p>The brain, as a reservoir of human immunodeficiency virus (HIV), has received tremendous attention due to the association with the brain’s infection with HIV-associated neurocognitive disorders (HAND). Along with the blood-brain barrier (BBB), heterogeneity across the various regions inside the brain makes HIV infection particularly complex to identify the ideal treatment for controlling HIV in the brain. In this study, we developed a mathematical model to describe the spatiotemporal dynamics of HIV infection in three essential regions of the brain: the prefrontal cortex (PF), the choroid plexus (CP), and the primary visual cortex (V1). We use our model to study the impact of drug pharmacodynamics and the CPE score (a permeability index for drugs into the brain) on viral control in the brain. The infection invasion threshold, which we theoretically established as the determinant of infection avoidance or virus persistence, enables us to select drugs for treatment protocols with pharmacodynamic properties (dose-response curve slope, dose, half-life, dose interval, CPE score) that prevent and control HIV infection in the brain. Our novel model and related theoretical and numerical results provide further insights into the impact of antiretroviral therapy on the spatiotemporal dynamics of HIV infection in the brain.</p>