The C-C chemokine receptor 5 (CCR5) is a seven-transmembrane G protein-coupled receptor that mediates HIV virus cellular entry. Individuals who are homozygous for a 32 base pair deletion in the CCR5 gene (CCR5D32), and subsequently do not express functional CCR5, are highly protected from infection with R5 HIV-1. The receptor is expressed in microglia, astrocytes and neurons in many regions of the brain. Dr. Alcino Silva at UCLA postulates that this receptor is involved in learning and memory. In a series of elegant experiments, he showed 1) CCR5 deficiency results in enhancements in hippocampal learning and memory and in experience-dependent sensory plasticity; and 2) CCR5 overexpression leads to learning and memory deficits. Decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation, hippocampus-dependent memory, and neocortical experience-dependent plasticity. Ligand binding to CCR5 is known to modulate several parallel signaling cascades implicated in learning and memory, including the suppression of adenyl cyclase, as well as the activation of the PI3K/AKT and P44/42 MAPK signaling. These findings support the application of brain permeable CCR5 antagonists, not only as a combination drug in antiretroviral therapy, but also as a treatment for cognitive deficits caused by HIV. In addition, the studies suggest that the receptor is a novel target to augment learning and memory in those with cognitive and motor deficits in relation to training.