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Aging is a risk factor for amyloid beta (Aβ) accumulation and dementia. Since highly active antiretroviral therapies have effectively lengthened the life expectancy of individuals infected with HIV-1, we investigated the affect of HIV-1 Tat, a viral transactivating transcription factor, on Aβ degradation in the brain by neprilysin (NEP), a neuronal endopeptidase.Using neural cell membrane fractions from human brain aggregates, Tat inhibition of NEP activity was assessed in a fluorescence assay. Following treatment with Tat, conditioned medium of human brain aggregate cultures was assayed for Aβ1–40 by ELISA. We evaluated the potential consequence of Tat inhibition of NEP by immunostaining cortex sections from postmortem human brain for Aβ.In an in vitro assay, Tat inhibited NEP activity by 80%. The cysteine-rich domain of Tat was essential for NEP inhibition. Recombinant Tat added directly to brain cultures, resulted in a 125% increase in soluble Aβ. Postmortem human brain sections from patients with HIV-1 infection (n = 14; 31–58 years old) had a significant increase in Aβ, compared to controls (n = 5; 30–52 years old). Correlative analysis identified a statistically significant relationship between Aβ load and duration of HIV-1 seropositive status.We have shown that Tat, which is found in the brains of patients with HIV-1 infection, inhibits the Aβ-degrading enzyme, NEP. Aβ staining was significantly increased in human brain sections from individuals with HIV-1 infection compared to controls. These results have important implications for individuals living and aging with HIV-1 infection.