Many recent studies indicate that dysregulation of autophagy is a common feature of many neurodegenerative diseases. The HIV-1-associated neurological disorder is an acquired cognitive and motor disease that includes a severe neurodegenerative dementia. We find that the neurodegeneration seen in the brain in HIV-1 infection is associated with an inhibition of neuronal autophagy, leading to neuronal demise. Neurons treated with supernatants from SIV-infected microglia develop a decrease in autophagy-inducing proteins, a decrease in neuronal autophagy vesicles, and an increase in sequestosome-1/p62. Examination of brains from HIV-infected individuals and SIV-infected monkeys reveals signs of autophagy dysregulation, associated, respectively, with dementia and encephalitis. Excitotoxic and inflammatory factors could inhibit neuronal autophagy, and stimulation of autophagy with rapamycin prevents such effects. Here we amplify on these findings, and propose that in the setting of HIV-infection, the decreased neuronal autophagy sensitizes cells to pro-apoptotic and other damaging mechanisms, leading to neuronal dysfunction and death. Hence, new therapeutic approaches aimed at boosting neuronal autophagy are conceivable to treat those suffering from the neurological complications of HIV.