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HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated with the early transmigration of HIV-infected monocytes across the BBB in a CCL2 and HIV replication-dependent manner. However, the mechanisms of chronic brain damage are unknown. We demonstrate that all PWH under ART have elevated circulating ATP levels that correlate with the onset of cognitive impairment even in the absence of a circulating virus. Serum ATP levels found in PWH with the most severe neurocognitive impairment trigger the transcellular migration of HIV-infected leukocytes across the BBB in a JAM-A and LFA-1-dependent manner. We propose that targeting transcellular leukocyte transmigration could reduce or prevent the devastating consequences of HIV within the brains of PWH under ART., Competing Interests: The authors do not have any conflicts of interest., (© 2024 The Authors.)